ADAMTS-1, ADAMTS-5 and ADAMTS-13 are considered potential targets in the treatment of frozen shoulder

ADAMTS-1, ADAMTS-5 and ADAMTS-13 are considered potential targets in the treatment of frozen shoulder | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article ADAMTS-1, ADAMTS-5 and ADAMTS-13 are considered potential targets in the treatment of frozen shoulder Zihao Zhou, Guanhong Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6401117/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Nov, 2025 Read the published version in Journal of Orthopaedic Surgery and Research → Version 1 posted 12 You are reading this latest preprint version Abstract Background Frozen shoulder (FS) is a condition that causes shoulder pain and restricted movement, primarily due to inflammation, fibrosis, and adhesion of the shoulder joint capsule. It commonly affects individuals aged 30 to 60 years. Factors such as diabetes, obesity, and shoulder trauma are known risk factors. Although current treatments include nonsteroidal anti-inflammatory drugs, steroid injections, and physical therapy, approximately 22.5% of patients do not respond well to conservative treatments and may require surgical intervention. The ADAMTS family is thought to play a significant role in joint diseases, and this study investigates its impact on FS. Methods This study employed the Mendelian Randomization (MR) analysis method using genome-wide association studies (GWAS) data to analyze the causal relationships between the ADAMTS-5 and ADAMTS-13 genes and FS. By screening SNPs related to ADAMTS-1, ADAMTS-5, and ADAMTS-13, data analysis was performed using R software to verify the impact of these genes on FS pathogenesis. Additionally, co-location analysis was conducted to identify potential therapeutic targets. Results The MR analysis results indicate that ADAMTS-1-mediated ADAMTS-5 levels, along with the levels of ADAMTS-5 and ADAMTS-13 themselves, significantly increase the risk of FS. Co-expression localization analysis revealed that rs62217270, rs977151, and rs4962153 are potential targets for inhibiting ADAMTS-1, ADAMTS-5, and ADAMTS-13, respectively. Conclusion This study demonstrates that increased activity of the ADAMTS family may exacerbate the pathological changes in FS, and targeting the inhibition of these genes could offer a new direction for FS intervention. This research provides potential targeted therapeutic approaches for FS treatment and lays the foundation for future clinical studies. Mendelian randomization Frozen shoulder Pathogenesis Inflammation Fibrosis Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Frozen shoulder (FS) is a condition that causes significant pain and restricted movement in the shoulder, primarily due to inflammation, fibrosis, and adhesion of the shoulder joint capsule( 1 ). FS most commonly affects individuals between the ages of 30 and 60 years, with several risk factors being strongly associated with its onset, including diabetes, obesity, and shoulder trauma( 2 ). Current research has consistently highlighted these factors as contributing to the development of FS. The pathogenesis of FS, however, remains incompletely understood. Current studies suggest that it is largely driven by immune system responses and chronic inflammation. In particular, the activation of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α, along with the involvement of growth factors and fibroblasts, leads to the progressive fibrosis and eventual adhesion of the joint capsule, which restricts movement and causes pain( 3 , 4 ). Despite ongoing research, a comprehensive understanding of how these biological processes interact in FS remains an area of active investigation. Treatment for FS typically includes nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular steroid injections, and physical therapy (such as stretching exercises) aimed at improving range of motion. While most patients respond well to conservative treatment, approximately 22.5% of individuals do not experience adequate relief and may require surgical intervention( 5 ). Therefore, early diagnosis and appropriate treatment are crucial for restoring shoulder function. The ADAMTS family is considered to play a crucial role in the pathogenesis of joint diseases, including tear repair( 6 ). Previous studies have shown that the ADAMTS family is not only involved in the fibrosis processes of the heart, kidneys, and lungs but also associated with inflammatory responses( 7 – 10 ). Therefore, we hypothesize that increased activity of the ADAMTS family may exacerbate pathological changes in FS, and targeted therapies aimed at inhibiting these enzymes could provide new directions for FS intervention. Previous observational studies are often susceptible to the influence of confounding factors, mixed factors, and biases, which can limit the accuracy of causal inference. As a research method similar to randomized controlled trials, Mendelian Randomization (MR) effectively avoids these biases by using genetic variants as instrumental variables, enabling more accurate identification of the causal relationship between exposure factors and diseases( 11 ). For this purpose, this study utilized large-scale genome-wide association studies (GWAS) data to further investigate the impact of the ADAMTS family on FS and identify potential therapeutic targets. We conducted MR studies with ADAMTS-5 and ADAMTS-13 as exposure factors and FS as the outcome. METHODS To mitigate potential confounding bias caused by racial stratification, our study focuses solely on participants of European ancestry, ensuring the reliability and consistency of the results. Data acquisition We obtained the positions of the ADAMTS-1, ADAMTS-5, and ADAMTS-13 genes from the official National Library of Medicine website (ncbi.nlm.nih.gov/gene/), conducting co-location analysis of nucleotides within 5000 kb around these genes. Data related to ADAMTS-5 (including 5,362 Europeans), ADAMTS-13 (including 5,359 Europeans), and FS (including 451,099 Europeans) as exposure factors were all obtained from the GWAS catalog (ebi.ac.uk). Selection of instrumental variables The selected instrumental variables (IVs) must meet the three fundamental principles of Mendelian Randomization (MR) analysis: correlation, independence, and exclusion of confounding. Therefore, we set the screening criteria for exposure factors as P 10,000 kb, and an F > 10( 12 ). Finally, when aligning exposure with outcome data, we removed palindromic Single Nucleotide Polymorphisms (SNPs) with intermediate allele frequencies and excluded SNPs associated with outcomes or confounding factors( 13 ). Due to insufficient IVs obtained when screening SNPs for the exposure factors ADAMTS-5 and ADAMTS-13, we relaxed the screening criteria by raising the threshold to P < 5 × 10 − 6 . Mendelian randomization analysis In this study, we used the TwoSampleMR package in R software (version 4.4.2) for data analysis to examine the impact of ADAMTS-1-targeted inhibition on ADAMTS-5 in FS pathogenesis, as well as the effects of directly inhibiting ADAMTS-5 and ADAMTS-13 on FS pathogenesis. The instrumental variable regression (IVW) method was the primary analytical approach for testing causal relationships and minimizing confounding bias( 14 ). Additionally, supplementary methods such as MR Egger, weighted median, simple mode, and weighted mode were used to assess the robustness of the IVW results. To evaluate heterogeneity in the IVW results, Cochran Q-tests were incorporated. We also calculated Egger-intercept values to detect directional multiplicity and confounding effects, and used the MR-PRESSO method to identify and remove potential outliers( 15 ). To assess the impact of individual SNPs on the causal relationship between exposure and outcome, we performed leave-one-out analysis. Finally, to more intuitively evaluate the reliability of our results, we plotted funnel plots, scatterplots, and forest plots. Co-location analysis To further explore the common targets between LDL and FS, we searched for the ADAMTS-5 and ADAMTS-13 numbers in the GWAS database on the eQTL website (eqtlgen.org/cis-eqtls.html), and then found the corresponding databases (eqtl-a-ENSG00000154736 and eqtl-a-ENSG00000154734) on the IEU OpenGWAS official website (mrcieu.ac.uk). Next, we used the locuscomparer and gassocplot packages in R to perform co-location analysis with FS, aiming to identify potential therapeutic targets. Ethics statement All included research data are publicly available from the official websites of MRC-IEU and the GWAS catalog. Since all the data used in this study are derived from previous research, no further ethical review is required. RESULTS Instrumental variables For the two target genes, ADAMTS-1 and ADAMTS-5, we ultimately screened 19 and 23 SNPs related to ADAMTS-5, respectively, as IVs for MR analysis. For ADAMTS-13, we identified a total of 19 SNPs related to it as IVs for MR analysis. Drug target Mendelian randomization analysis The confidence intervals (CIs) for the IVW analysis of ADAMTS-1-targeted inhibition of ADAMTS-5-mediated metabolism and the IVW analysis of ADAMTS-13 affecting FS pathogenesis do not include 1, with all * P < 0.05. The DrugOR values from the five MR analysis methods are all < 1. Similarly, the CIs of the Weighted median and IVW for the impact of ADAMTS-5-targeted inhibition on FS pathogenesis also do not include 1, with * P < 0.05, and the DrugOR values from all five MR methods are < 1. Based on the IVW results for these three targets, we conclude that targeting these genes may lead to statistically significant reductions in FS pathogenesis (Table I). Additionally, the Egger intercepts for these three target genes are 0.05, and the Cochran Q-test for heterogeneity also shows P > 0.05, indicating that the results are not significantly affected by heterogeneity (Table II). Forest plots (Fig. 2 A, 2 B, and 2 C), funnel plots (Fig. 2 D, 2 E, and 2 F), leave-one-out analyses (Fig. 2 G, 2 H, and 2 I), scatter plots (Fig. 2 J, 2 K, and 2 L), and forest plots from the five MR analyses (Fig. 3 A, 3 B, and 3 C) further support our findings. In particular, the funnel plots for the three target genes show even distribution of points at both ends of the line, indicating minimal heterogeneity. Forest plots and leave-one-out analyses reveal that the IVW intervals for the three target genes are all to the right of the dashed line, suggesting that ADAMTS-1-mediated increases in ADAMTS-5, ADAMTS-5, and ADAMTS-13 levels all contribute to an increased risk of FS. The scatter plots further confirm that ADAMTS-1 mediates the increase in ADAMTS-5 levels, as well as the levels of ADAMTS-5 and ADAMTS-13, which all increase the risk of FS. Co-location analysis Using the locuscomparer and gassocplot packages in R software, along with the gene loci of ADAMTS-1, ADAMTS-5, and ADAMTS-13, we conducted co-location analyses of these three target genes with their corresponding exposure factors and the outcome (FS). Our analysis identified rs62217270 as a potential target for inhibiting the action of ADAMTS-1 on ADAMTS-5, thereby influencing the onset of FS ( Fig. 4 A). Additionally, rs977151 and rs4962153 are potential targets for inhibiting ADAMTS-5 and ADAMTS-13, respectively, to impact the onset of FS (Fig. 4 B and 4 C). DISCUSSION ADAMTS-1, ADAMTS-5, and ADAMTS-13 are three members of the matrix metalloproteinase family, which play crucial roles in various physiological and pathological processes. In recent years, research into their roles in joint diseases has increased( 16 ). FS is a typical shoulder joint disease caused by chronic inflammation and fibrosis, resulting in restricted joint movement and severe pain. Members of the ADAMTS family are involved in the metabolic regulation of articular cartilage and connective tissue, particularly in the pathological processes related to inflammation and fibrosis( 17 ). In our study, we found that targeted inhibition of ADAMTS-1 can influence the metabolism of ADAMTS-5, thereby reducing the risk of FS. Additionally, targeted inhibition of both ADAMTS-5 and ADAMTS-13 is also associated with a reduced risk of developing FS. All three findings are supported by statistical evidence. However, further investigation is required to better understand how these factors contribute to the pathogenesis of FS. ADAMTS-1, known as the "aggregating enzyme," is associated with various types of arthritis, particularly cartilage degeneration and fibrosis( 17 ). Based on previous research, we hypothesize that ADAMTS-1 plays a crucial role in the pathological state of FS. On one hand, it may promote cartilage degeneration by degrading the cartilage matrix( 10 ). On the other hand, it may contribute to the fibrosis process through its effects on other matrix proteins, such as aggrecan and proteoglycans. Upregulation of ADAMTS-1 may also exacerbate the synovial inflammatory response in the early stages of adhesive capsulitis, potentially driving the disease toward fibrosis( 17 ). ADAMTS-5 also plays an important metabolic role in cartilage, primarily by cleaving aggrecan, a process that helps inhibit joint fibrosis( 18 ). However, in FS, the overactivation of ADAMTS-5 may intensify extracellular matrix degradation, worsening joint inflammation and synovitis, which further promotes the fibrosis of the joint capsule( 10 ). Moreover, existing research indicates that factors such as obesity and age indirectly affect the expression of ADAMTS-5 through pro-inflammatory mechanisms, thereby influencing the occurrence and development of FS. For example, the increased expression of pro-inflammatory cytokines such as IL-1β and TNF-α can upregulate the expression of ADAMTS-5, further exacerbating the pathogenesis of FS( 10 , 19 ). This creates a positive feedback loop that intensifies the vicious cycle between ADAMTS-5 and synovitis, promoting the progression of FS. Moreover, studies indicate a high degree of homology between ADAMTS-1 and ADAMTS-5, which may explain why targeting the inhibition of ADAMTS-1 also affects ADAMTS-5 levels, thereby impacting the pathogenesis of FS( 20 , 21 ). This aligns with our experimental results.But further investigation is needed to explore the relationship between ADAMTS-5 and FS pathogenesis. ADAMTS-13, primarily associated with thrombotic disorders such as thrombotic thrombocytopenic purpura (TTP), regulates blood coagulation by cleaving ultralarge von Willebrand factor (UL-VWF)( 22 ). Studies have shown that patients with FS often experience circulatory abnormalities, especially during inflammatory responses, where hypoxia in the synovium exacerbates the inflammatory response( 3 ). ADAMTS-13 may play a role in inhibiting angiogenesis during this process, which could synergistically worsen the hypoxic state of the shoulder joint, thereby affecting its repair and recovery( 23 ). However, previous studies have shown that mutations in vWF can lead to the inability of fibrin to liquefy and degrade, resulting in intravascular coagulation and thrombosis, which causes vascular occlusion( 24 ). When the level of ADAMTS-13 in the body decreases, UL-vWF accumulates in the plasma, promoting platelet aggregation and triggering thrombotic inflammation( 20 ). For example, platelets can form platelet-leukocyte aggregates (PLAs) through interactions with white blood cells, which promotes the recruitment and activation of inflammatory cells, exacerbates local inflammatory reactions, and increases the risk of secondary thrombotic events and tissue damage( 25 ). This seems to contradict our research findings. Therefore, we believe that further research is needed to confirm the role of ADAMTS-13 in the pathogenesis of FS. We are the first to apply Mendelian randomization to investigate the impact of the ADAMTS family on the pathogenesis of FS and to confirm potential therapeutic targets. Our experiment has the following advantages. First, we utilized large-scale GWAS data for MR analysis, significantly reducing bias that may arise from clinical observational studies. Second, we found that targeted inhibition of ADAMTS-1, ADAMTS-5, and ADAMTS-13 can significantly reduce the risk of developing FS. However, our experiment also has some limitations. First, our MR analysis used data primarily from European and American populations, which may introduce racial bias. Second, the relatively small number of instrumental variables (IVs) used in the MR analysis could lead to experimental bias. Third, the analysis results for ADAMTS-13 appear to conflict with previous experimental findings, and further verification in future studies is necessary. Given the important role of ADAMTS family members in the pathogenesis of FS, researchers have begun to explore the potential of modulating their activity as a therapeutic approach for frozen shoulder. For example, inhibiting the excessive activity of ADAMTS-1 and ADAMTS-5 may help slow the fibrosis process in the joint capsule and preserve normal joint function. Additionally, targeting ADAMTS-13 may provide new insights into FS treatment, particularly in regulating angiogenesis and inflammatory responses.As research on the role of ADAMTS family members in FS pathogenesis advances, specific inhibitors of these enzymes may emerge as a promising new strategy for treating frozen shoulder. In conclusion, our experiments suggest that ADAMTS-1, ADAMTS-5, and ADAMTS-13 contribute to the increased risk of FS onset. Specifically, rs62217270 is identified as a potential target for inhibiting ADAMTS-1, which in turn affects ADAMTS-5 and influences FS onset. Additionally, rs977151 and rs4962153 are potential targets for inhibiting ADAMTS-5 and ADAMTS-13, respectively, to impact the onset of FS. Declarations Acknowledgements Notapplicable Funding No funding was received. Availability of data and materials The dataset generated in the present study may be found at the following URLs: mrcieu.ac.uk and the ebi.ac.uk. Authors’ contributions Zihao Zhou was responsible for writing the entire manuscript, creating the tables, and generating the figures. Guanhong Chen was responsible for the manuscript review. Ethics approval and consent to participate Since the data used in our study were all obtained from existing databases, no additional ethical review is required for our research. Patient consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Author Contributions (Use CRediT terms) Dr. Zhou Zihao completed the writing of all the papers, as well as the production of images and tables. Professor Chen Guanhong has completed the review and correction of the grammar and image quality of all papers. ORCID iDs Zihao Zhou https://orcid.org/0000-0003-0655-3960 Guanhong Chen https://orcid.org/0000-0001-9545-8214 References Chul-Hyun C, Yong-Ho L, Du-Hwan K, Young-Jae L, Chung-Sin B, Du-Han K, Definition. Diagnosis, Treatment, and Prognosis of Frozen Shoulder: A Consensus Survey of Shoulder Specialists. Clin Orthop Surg. 2020;12(1). Shuquan T, Xiaoya T. Does the intervention for adhesive capsulitis in patients with diabetes differ from that for patients without diabetes? A systematic review. Med (Baltim). 2024;103:46. Daniel dlS, Santiago N-L, Fany A, Elena L, Leo P. A Comprehensive View of Frozen Shoulder: A Mystery Syndrome. Front Med (Lausanne). 2021;8(0). Yun-Mee L, Eunyoung H, Chul-Hyun C et al. 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Tables Table I Drug target Mendelian randomization analysis results of FS. outcome exposure method nsnp pval or or_lci95 or_uci95 orDrug or_lci95Drug or_uci95Drug FS ADAMTS-1 MR Egger 19 0.413071653715278 1.01619478056092 0.978767240306829 1.05505353010746 0.984063310626353 0.947819206763989 1.02169336980109 FS ADAMTS-1 Weighted median 19 0.0559822803460556 1.03062224564626 0.999229702624722 1.06300104013207 0.97028761432657 0.940732851847219 1.00077089119074 FS ADAMTS-1 Inverse variance weighted 19 0.00424222419569982 1.04031775937388 1.01251182179604 1.06888731288976 0.96124476487055 0.935552314954958 0.987642789420627 FS ADAMTS-1 Simple mode 19 0.0819905754456494 1.05821431826417 0.996386600028157 1.12387856615861 0.944988158580523 0.889775844215959 1.00362650398123 FS ADAMTS-1 Weighted mode 19 0.0637368823733314 1.03401745061736 1.00026402656448 1.06890986758115 0.967101666807413 0.935532574194415 0.999736043127146 FS ADAMTS-5 MR Egger 23 0.392694046606961 1.01526479709541 0.981302396033404 1.05040262042333 0.984964713502253 0.952015903765536 1.01905386559961 FS ADAMTS-5 Weighted median 23 0.0477303130724897 1.03052632923893 1.00030019607459 1.06166580734678 0.970377924005613 0.941915990022424 0.999699894016053 FS ADAMTS-5 Inverse variance weighted 23 0.00363342762514621 1.03158192849035 1.01019047457168 1.05342636064655 0.969384953712243 0.949283250692759 0.989912323637773 FS ADAMTS-5 Simple mode 23 0.174923223945707 1.0354603344021 0.98622042173187 1.08715869241209 0.965754038832806 0.91982891456379 1.01397210802422 FS ADAMTS-5 Weighted mode 23 0.0752122153095228 1.03021864792613 0.998526503993596 1.06291666599724 0.970667733507867 0.940807527052735 1.00147567040085 FS ADAMTS-13 MR Egger 19 0.656294955530936 1.01181436581668 0.961678129492346 1.06456441035365 0.988323583637649 0.939351334944402 1.03984895708077 FS ADAMTS-13 Weighted median 19 0.163976241971478 1.0275444108972 0.988969025331487 1.06762445468115 0.973193946066866 0.936658949329383 1.01115401431791 FS ADAMTS-13 Inverse variance weighted 19 0.035206769263585 1.03070915846205 1.00209872764253 1.06013643170347 0.970205796455842 0.943274818311032 0.997905667790375 FS ADAMTS-13 Simple mode 19 0.0834531468354106 1.05475151834128 0.996302132106538 1.1166299153561 0.948090600118425 0.895551862123533 1.00371159287358 FS ADAMTS-13 Weighted mode 19 0.287172194396276 1.02741971881872 0.978937193745352 1.07830337366069 0.973312057072207 0.927382798224155 1.02151599345619 Table II Heterogeneity and pleiotropy tests. exposure outcome method Q_pval egger_intercept se pval ADAMTS-1 FS MR Egger 0.333402403452115 0.0128291316407622 0.00760262681657752 0.109775221998388 ADAMTS-1 FS Inverse variance weighted 0.228281467427927 ADAMTS-5 FS MR Egger 0.470058079490945 0.00713386669190691 0.00613368931737666 0.257850254616823 ADAMTS-5 FS Inverse variance weighted 0.449693027779464 ADAMTS-13 FS MR Egger 0.990022301183422 0.00678442727509325 0.00791589612503133 0.403330433055831 ADAMTS-13 FS Inverse variance weighted 0.988893246270022 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 18 Nov, 2025 Read the published version in Journal of Orthopaedic Surgery and Research → Version 1 posted Editorial decision: Revision requested 08 May, 2025 Reviews received at journal 07 May, 2025 Reviewers agreed at journal 22 Apr, 2025 Reviewers agreed at journal 22 Apr, 2025 Reviews received at journal 21 Apr, 2025 Reviewers agreed at journal 21 Apr, 2025 Reviews received at journal 14 Apr, 2025 Reviewers agreed at journal 08 Apr, 2025 Reviewers invited by journal 08 Apr, 2025 Editor assigned by journal 08 Apr, 2025 Submission checks completed at journal 08 Apr, 2025 First submitted to journal 08 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6401117","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":440364712,"identity":"9674dd3e-a2a1-4a11-b82d-98ee9784c6a9","order_by":0,"name":"Zihao Zhou","email":"","orcid":"","institution":"Liaoning Provincial People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zihao","middleName":"","lastName":"Zhou","suffix":""},{"id":440364716,"identity":"66159753-3920-4837-9bdb-3611bcc73e25","order_by":1,"name":"Guanhong Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYBACeYaDDQcSKtjs+InWYth4uPHAhzN8yZINROs5fLz54Mw2OcYNB4jVwdh2sOEwD5sZs/Hx5A0MPyq2EdbCzgPSwpPGZ3bmWQFjz5nbRNgyA6RF4hiz2Y0cA2bGNiK0MNx/CNRi8J9x8wyitRw42HBwRgIb4wYJYrUYNgDj5cMBtmQJoF8OEuUXeYbjjz8k/gNGZXvyxgc/KohxGAIkGBwgST1YC6k6RsEoGAWjYIQAAMcFRjQgk+iPAAAAAElFTkSuQmCC","orcid":"","institution":"Shan County Central Hospital","correspondingAuthor":true,"prefix":"","firstName":"Guanhong","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2025-04-08 08:38:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6401117/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6401117/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13018-025-06002-9","type":"published","date":"2025-11-18T15:58:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80712152,"identity":"4e4762a1-b32b-48be-b561-2a12c985ed40","added_by":"auto","created_at":"2025-04-16 09:13:28","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45966,"visible":true,"origin":"","legend":"\u003cp\u003eExperimental flowchart.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6401117/v1/66f27c05b437cd4546e36bc9.jpeg"},{"id":80712156,"identity":"59968650-adc8-450e-8a36-28841e4885d2","added_by":"auto","created_at":"2025-04-16 09:13:29","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":61565,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots (A, B, and C), funnel plots (Fig D, E, and F), leave-one-out analyses (Fig G, H, and I), scatter plots (Fig J, K, and L) of Drug target Mendelian randomization.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6401117/v1/1cdaf092442e7a3095093acf.jpeg"},{"id":80712991,"identity":"6ce4ec2c-17e3-41d1-8bcb-ad16cfa348ef","added_by":"auto","created_at":"2025-04-16 09:21:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":274873,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of 5 TwoSampleMR analyses.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6401117/v1/ab308803d9be6daaaeb923fc.png"},{"id":80712160,"identity":"6a142344-1f18-488f-bd72-794c37ff555b","added_by":"auto","created_at":"2025-04-16 09:13:29","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":364147,"visible":true,"origin":"","legend":"\u003cp\u003eCo-location analysis of ADAMTS-1(A), ADAMTS-5(B), ADAMTS-13(C).\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6401117/v1/58f670aade70d5dba124339f.jpeg"},{"id":96650355,"identity":"4fea4d4c-d4e4-4af2-b398-703f503df821","added_by":"auto","created_at":"2025-11-24 16:11:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1395057,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6401117/v1/ff6a7d88-4789-4240-86a2-855e104da2af.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"ADAMTS-1, ADAMTS-5 and ADAMTS-13 are considered potential targets in the treatment of frozen shoulder","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eFrozen shoulder (FS) is a condition that causes significant pain and restricted movement in the shoulder, primarily due to inflammation, fibrosis, and adhesion of the shoulder joint capsule(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). FS most commonly affects individuals between the ages of 30 and 60 years, with several risk factors being strongly associated with its onset, including diabetes, obesity, and shoulder trauma(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Current research has consistently highlighted these factors as contributing to the development of FS. The pathogenesis of FS, however, remains incompletely understood. Current studies suggest that it is largely driven by immune system responses and chronic inflammation. In particular, the activation of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α, along with the involvement of growth factors and fibroblasts, leads to the progressive fibrosis and eventual adhesion of the joint capsule, which restricts movement and causes pain(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Despite ongoing research, a comprehensive understanding of how these biological processes interact in FS remains an area of active investigation. Treatment for FS typically includes nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular steroid injections, and physical therapy (such as stretching exercises) aimed at improving range of motion. While most patients respond well to conservative treatment, approximately 22.5% of individuals do not experience adequate relief and may require surgical intervention(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Therefore, early diagnosis and appropriate treatment are crucial for restoring shoulder function.\u003c/p\u003e \u003cp\u003eThe ADAMTS family is considered to play a crucial role in the pathogenesis of joint diseases, including tear repair(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Previous studies have shown that the ADAMTS family is not only involved in the fibrosis processes of the heart, kidneys, and lungs but also associated with inflammatory responses(\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Therefore, we hypothesize that increased activity of the ADAMTS family may exacerbate pathological changes in FS, and targeted therapies aimed at inhibiting these enzymes could provide new directions for FS intervention.\u003c/p\u003e \u003cp\u003ePrevious observational studies are often susceptible to the influence of confounding factors, mixed factors, and biases, which can limit the accuracy of causal inference. As a research method similar to randomized controlled trials, Mendelian Randomization (MR) effectively avoids these biases by using genetic variants as instrumental variables, enabling more accurate identification of the causal relationship between exposure factors and diseases(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). For this purpose, this study utilized large-scale genome-wide association studies (GWAS) data to further investigate the impact of the ADAMTS family on FS and identify potential therapeutic targets. We conducted MR studies with ADAMTS-5 and ADAMTS-13 as exposure factors and FS as the outcome.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eTo mitigate potential confounding bias caused by racial stratification, our study focuses solely on participants of European ancestry, ensuring the reliability and consistency of the results.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData acquisition\u003c/h2\u003e \u003cp\u003eWe obtained the positions of the ADAMTS-1, ADAMTS-5, and ADAMTS-13 genes from the official National Library of Medicine website (ncbi.nlm.nih.gov/gene/), conducting co-location analysis of nucleotides within 5000 kb around these genes. Data related to ADAMTS-5 (including 5,362 Europeans), ADAMTS-13 (including 5,359 Europeans), and FS (including 451,099 Europeans) as exposure factors were all obtained from the GWAS catalog (ebi.ac.uk).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSelection of instrumental variables\u003c/h3\u003e\n\u003cp\u003eThe selected instrumental variables (IVs) must meet the three fundamental principles of Mendelian Randomization (MR) analysis: correlation, independence, and exclusion of confounding. Therefore, we set the screening criteria for exposure factors as \u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u0026lt;\u0026thinsp;5 \u0026times; 10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e, a linkage disequilibrium coefficient (r\u0026sup2;) of 0.001, a linkage disequilibrium region width\u0026thinsp;\u0026gt;\u0026thinsp;10,000 kb, and an F\u0026thinsp;\u0026gt;\u0026thinsp;10(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Finally, when aligning exposure with outcome data, we removed palindromic Single Nucleotide Polymorphisms (SNPs) with intermediate allele frequencies and excluded SNPs associated with outcomes or confounding factors(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Due to insufficient IVs obtained when screening SNPs for the exposure factors ADAMTS-5 and ADAMTS-13, we relaxed the screening criteria by raising the threshold to \u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u0026lt;\u0026thinsp;5 \u0026times; 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eMendelian randomization analysis\u003c/h3\u003e\n\u003cp\u003eIn this study, we used the TwoSampleMR package in R software (version 4.4.2) for data analysis to examine the impact of ADAMTS-1-targeted inhibition on ADAMTS-5 in FS pathogenesis, as well as the effects of directly inhibiting ADAMTS-5 and ADAMTS-13 on FS pathogenesis. The instrumental variable regression (IVW) method was the primary analytical approach for testing causal relationships and minimizing confounding bias(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Additionally, supplementary methods such as MR Egger, weighted median, simple mode, and weighted mode were used to assess the robustness of the IVW results.\u003c/p\u003e \u003cp\u003eTo evaluate heterogeneity in the IVW results, Cochran Q-tests were incorporated. We also calculated Egger-intercept values to detect directional multiplicity and confounding effects, and used the MR-PRESSO method to identify and remove potential outliers(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). To assess the impact of individual SNPs on the causal relationship between exposure and outcome, we performed leave-one-out analysis. Finally, to more intuitively evaluate the reliability of our results, we plotted funnel plots, scatterplots, and forest plots.\u003c/p\u003e\n\u003ch3\u003eCo-location analysis\u003c/h3\u003e\n\u003cp\u003eTo further explore the common targets between LDL and FS, we searched for the ADAMTS-5 and ADAMTS-13 numbers in the GWAS database on the eQTL website (eqtlgen.org/cis-eqtls.html), and then found the corresponding databases (eqtl-a-ENSG00000154736 and eqtl-a-ENSG00000154734) on the IEU OpenGWAS official website (mrcieu.ac.uk). Next, we used the locuscomparer and gassocplot packages in R to perform co-location analysis with FS, aiming to identify potential therapeutic targets.\u003c/p\u003e\n\u003ch3\u003eEthics statement\u003c/h3\u003e\n\u003cp\u003eAll included research data are publicly available from the official websites of MRC-IEU and the GWAS catalog. Since all the data used in this study are derived from previous research, no further ethical review is required.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eInstrumental variables\u003c/h2\u003e \u003cp\u003eFor the two target genes, ADAMTS-1 and ADAMTS-5, we ultimately screened 19 and 23 SNPs related to ADAMTS-5, respectively, as IVs for MR analysis. For ADAMTS-13, we identified a total of 19 SNPs related to it as IVs for MR analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDrug target Mendelian randomization analysis\u003c/h3\u003e\n\u003cp\u003eThe confidence intervals (CIs) for the IVW analysis of ADAMTS-1-targeted inhibition of ADAMTS-5-mediated metabolism and the IVW analysis of ADAMTS-13 affecting FS pathogenesis do not include 1, with all *\u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. The DrugOR values from the five MR analysis methods are all \u0026lt;\u0026thinsp;1. Similarly, the CIs of the Weighted median and IVW for the impact of ADAMTS-5-targeted inhibition on FS pathogenesis also do not include 1, with *\u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, and the DrugOR values from all five MR methods are \u0026lt;\u0026thinsp;1. Based on the IVW results for these three targets, we conclude that targeting these genes may lead to statistically significant reductions in FS pathogenesis (Table I).\u003c/p\u003e \u003cp\u003eAdditionally, the Egger intercepts for these three target genes are \u0026lt;\u0026thinsp;0.05, with \u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05, and the Cochran Q-test for heterogeneity also shows \u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05, indicating that the results are not significantly affected by heterogeneity (Table II). Forest plots (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), funnel plots (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE, and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF), leave-one-out analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eH, and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eI), scatter plots (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eJ, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eK, and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eL), and forest plots from the five MR analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB, and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC) further support our findings. In particular, the funnel plots for the three target genes show even distribution of points at both ends of the line, indicating minimal heterogeneity. Forest plots and leave-one-out analyses reveal that the IVW intervals for the three target genes are all to the right of the dashed line, suggesting that ADAMTS-1-mediated increases in ADAMTS-5, ADAMTS-5, and ADAMTS-13 levels all contribute to an increased risk of FS. The scatter plots further confirm that ADAMTS-1 mediates the increase in ADAMTS-5 levels, as well as the levels of ADAMTS-5 and ADAMTS-13, which all increase the risk of FS.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCo-location analysis\u003c/h2\u003e \u003cp\u003eUsing the locuscomparer and gassocplot packages in R software, along with the gene loci of ADAMTS-1, ADAMTS-5, and ADAMTS-13, we conducted co-location analyses of these three target genes with their corresponding exposure factors and the outcome (FS). Our analysis identified rs62217270 as a potential target for inhibiting the action of ADAMTS-1 on ADAMTS-5, thereby influencing the onset of FS ( Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). Additionally, rs977151 and rs4962153 are potential targets for inhibiting ADAMTS-5 and ADAMTS-13, respectively, to impact the onset of FS (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eADAMTS-1, ADAMTS-5, and ADAMTS-13 are three members of the matrix metalloproteinase family, which play crucial roles in various physiological and pathological processes. In recent years, research into their roles in joint diseases has increased(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). FS is a typical shoulder joint disease caused by chronic inflammation and fibrosis, resulting in restricted joint movement and severe pain. Members of the ADAMTS family are involved in the metabolic regulation of articular cartilage and connective tissue, particularly in the pathological processes related to inflammation and fibrosis(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In our study, we found that targeted inhibition of ADAMTS-1 can influence the metabolism of ADAMTS-5, thereby reducing the risk of FS. Additionally, targeted inhibition of both ADAMTS-5 and ADAMTS-13 is also associated with a reduced risk of developing FS. All three findings are supported by statistical evidence. However, further investigation is required to better understand how these factors contribute to the pathogenesis of FS.\u003c/p\u003e \u003cp\u003eADAMTS-1, known as the \"aggregating enzyme,\" is associated with various types of arthritis, particularly cartilage degeneration and fibrosis(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Based on previous research, we hypothesize that ADAMTS-1 plays a crucial role in the pathological state of FS. On one hand, it may promote cartilage degeneration by degrading the cartilage matrix(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). On the other hand, it may contribute to the fibrosis process through its effects on other matrix proteins, such as aggrecan and proteoglycans. Upregulation of ADAMTS-1 may also exacerbate the synovial inflammatory response in the early stages of adhesive capsulitis, potentially driving the disease toward fibrosis(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). ADAMTS-5 also plays an important metabolic role in cartilage, primarily by cleaving aggrecan, a process that helps inhibit joint fibrosis(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). However, in FS, the overactivation of ADAMTS-5 may intensify extracellular matrix degradation, worsening joint inflammation and synovitis, which further promotes the fibrosis of the joint capsule(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Moreover, existing research indicates that factors such as obesity and age indirectly affect the expression of ADAMTS-5 through pro-inflammatory mechanisms, thereby influencing the occurrence and development of FS. For example, the increased expression of pro-inflammatory cytokines such as IL-1β and TNF-α can upregulate the expression of ADAMTS-5, further exacerbating the pathogenesis of FS(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). This creates a positive feedback loop that intensifies the vicious cycle between ADAMTS-5 and synovitis, promoting the progression of FS. Moreover, studies indicate a high degree of homology between ADAMTS-1 and ADAMTS-5, which may explain why targeting the inhibition of ADAMTS-1 also affects ADAMTS-5 levels, thereby impacting the pathogenesis of FS(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). This aligns with our experimental results.But further investigation is needed to explore the relationship between ADAMTS-5 and FS pathogenesis.\u003c/p\u003e \u003cp\u003eADAMTS-13, primarily associated with thrombotic disorders such as thrombotic thrombocytopenic purpura (TTP), regulates blood coagulation by cleaving ultralarge von Willebrand factor (UL-VWF)(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Studies have shown that patients with FS often experience circulatory abnormalities, especially during inflammatory responses, where hypoxia in the synovium exacerbates the inflammatory response(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). ADAMTS-13 may play a role in inhibiting angiogenesis during this process, which could synergistically worsen the hypoxic state of the shoulder joint, thereby affecting its repair and recovery(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). However, previous studies have shown that mutations in vWF can lead to the inability of fibrin to liquefy and degrade, resulting in intravascular coagulation and thrombosis, which causes vascular occlusion(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). When the level of ADAMTS-13 in the body decreases, UL-vWF accumulates in the plasma, promoting platelet aggregation and triggering thrombotic inflammation(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). For example, platelets can form platelet-leukocyte aggregates (PLAs) through interactions with white blood cells, which promotes the recruitment and activation of inflammatory cells, exacerbates local inflammatory reactions, and increases the risk of secondary thrombotic events and tissue damage(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). This seems to contradict our research findings. Therefore, we believe that further research is needed to confirm the role of ADAMTS-13 in the pathogenesis of FS.\u003c/p\u003e \u003cp\u003eWe are the first to apply Mendelian randomization to investigate the impact of the ADAMTS family on the pathogenesis of FS and to confirm potential therapeutic targets. Our experiment has the following advantages. First, we utilized large-scale GWAS data for MR analysis, significantly reducing bias that may arise from clinical observational studies. Second, we found that targeted inhibition of ADAMTS-1, ADAMTS-5, and ADAMTS-13 can significantly reduce the risk of developing FS. However, our experiment also has some limitations. First, our MR analysis used data primarily from European and American populations, which may introduce racial bias. Second, the relatively small number of instrumental variables (IVs) used in the MR analysis could lead to experimental bias. Third, the analysis results for ADAMTS-13 appear to conflict with previous experimental findings, and further verification in future studies is necessary.\u003c/p\u003e \u003cp\u003eGiven the important role of ADAMTS family members in the pathogenesis of FS, researchers have begun to explore the potential of modulating their activity as a therapeutic approach for frozen shoulder. For example, inhibiting the excessive activity of ADAMTS-1 and ADAMTS-5 may help slow the fibrosis process in the joint capsule and preserve normal joint function. Additionally, targeting ADAMTS-13 may provide new insights into FS treatment, particularly in regulating angiogenesis and inflammatory responses.As research on the role of ADAMTS family members in FS pathogenesis advances, specific inhibitors of these enzymes may emerge as a promising new strategy for treating frozen shoulder.\u003c/p\u003e \u003cp\u003eIn conclusion, our experiments suggest that ADAMTS-1, ADAMTS-5, and ADAMTS-13 contribute to the increased risk of FS onset. Specifically, rs62217270 is identified as a potential target for inhibiting ADAMTS-1, which in turn affects ADAMTS-5 and influences FS onset. Additionally, rs977151 and rs4962153 are potential targets for inhibiting ADAMTS-5 and ADAMTS-13, respectively, to impact the onset of FS.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNotapplicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset generated in the present study may be found at the following URLs: mrcieu.ac.uk and the ebi.ac.uk.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZihao Zhou was responsible for writing the entire manuscript, creating the tables, and generating the figures. Guanhong Chen was responsible for the manuscript review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince the data used in our study were all obtained from existing databases, no additional ethical review is required for our research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions (Use CRediT terms)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Zhou Zihao completed the writing of all the papers, as well as the production of images and tables. Professor Chen Guanhong has completed the review and correction of the grammar and image quality of all papers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORCID iDs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZihao Zhou https://orcid.org/0000-0003-0655-3960\u003c/p\u003e\n\u003cp\u003eGuanhong Chen\u0026nbsp;https://orcid.org/0000-0001-9545-8214\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChul-Hyun C, Yong-Ho L, Du-Hwan K, Young-Jae L, Chung-Sin B, Du-Han K, Definition. Diagnosis, Treatment, and Prognosis of Frozen Shoulder: A Consensus Survey of Shoulder Specialists. Clin Orthop Surg. 2020;12(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShuquan T, Xiaoya T. Does the intervention for adhesive capsulitis in patients with diabetes differ from that for patients without diabetes? A systematic review. Med (Baltim). 2024;103:46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaniel dlS, Santiago N-L, Fany A, Elena L, Leo P. A Comprehensive View of Frozen Shoulder: A Mystery Syndrome. Front Med (Lausanne). 2021;8(0).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYun-Mee L, Eunyoung H, Chul-Hyun C et al. Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder. J Shoulder Elb Surg. 2012;22(5).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKiera K, Emily JC, Joseph WG, Xinning L. Shoulder adhesive capsulitis: epidemiology and predictors of surgery. J Shoulder Elb Surg. 2018;27(8).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakahiro I, Masaya T, Toru W, Yoshimasa S, Masahiro H, Akihiro S. Expression and distribution pattern of aggrecanases and miR-140s in the thickened synovia of shoulder joints in rotator cuff tears: A retrospective observational study. Med (Baltim). 2022;101(32).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRui-zhen ES, Ying-zhen C. Y, [Association between myocardial ADAMTS-1 expression and myocardial fibrosis in a murine model of viral myocarditis]. Zhonghua xin xue guan bing za zhi. 2007;35(9).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIvana Kovacevic V, Mario L, Marija BK et al. First Characterization of ADAMTS-4 in Kidney Tissue and Plasma of Patients with Chronic Kidney Disease-A Potential Novel Diagnostic Indicator. Diagnostics (Basel). 2022;12(3).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLijing L, Hong Q, Qingxin M, Xiang Z, Yingmin W, Jianbin H. [Sinomenine ameliorates bleomycin A5-induced pulmonary fibrosis by blocking the miR-21/ADAMTS-1 signaling pathway in rats]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2023;39(8).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTing L, Jie P, Qingqing L, Yuan S, Peijun Z, Liang H. The Mechanism and Role of ADAMTS Protein Family in Osteoarthritis. Biomolecules. 2022;12(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohn CL. Mendelian Randomization: A Powerful Tool to Illuminate Pathophysiologic Mechanisms. Mayo Clin Proc. 2023;98(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng Q, Yan X, Wenjun C. Causal effect between breast cancer and ovarian cancer: a two-sample mendelian randomization study. BMC Cancer. 2024;24(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeng-Fei Z, Zhao-Fen Z, Zheng-Yu L, Jin H, Jing-Jing R, Hong-Wei P. HMGCR as a promising molecular target for therapeutic intervention in aortic aneurisms: a mendelian randomization study. Nutr Metab (Lond). 2024;21(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChenyang Z, Jiaxin L, Ying Z et al. Causal effects of lipid-lowering drugs on inflammatory skin diseases: Evidence from drug target Mendelian randomisation. Exp Dermatol. 2024;33(9).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStephen B, Simon GT. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32(5).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharles JM. Inhibition of MMPs and ADAM/ADAMTS. Biochem Pharmacol. 2019;165(0).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eC-Y Y AC. L T. ADAMTS and ADAM metalloproteinases in osteoarthritis - looking beyond the 'usual suspects'. Osteoarthritis Cartilage. 2017;25(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeather S, Fraser MR, Charlotte JE, et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature. 2005;434:7033.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDi C, Jie S, Weiwei Z et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res. 2017;5(0).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTimothy JM, Suneel SA. ADAMTS proteins in human disorders. Matrix Biol. 2018(0).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIita MV, Noora N, Sandra B et al. Putative susceptibility locus on chromosome 21q for lumbar disc disease (LDD) in the Finnish population. J Bone Min Res. 2007;22(5).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCamila M, Spero RC. The role of ADAMTS13 testing in the diagnosis and management of thrombotic microangiopathies and thrombosis. Blood. 2018;132(9).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eX L Z. Structure-function and regulation of ADAMTS-13 protease. J Thromb Haemost. 2013(0).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun L, Li X, Sun Y, et al. LncRNA ANRIL regulates AML development through modulating the glucose metabolism pathway of AdipoR1/AMPK/SIRT1. Mol Cancer. 2018;17(1):127.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMadhumita C, Agnes E, Laura Mara T et al. Molecular Drivers of Platelet Activation: Unraveling Novel Targets for Anti-Thrombotic and Anti-Thrombo-Inflammatory Therapy. Int J Mol Sci. 2020;21(21).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;I Drug target Mendelian randomization analysis results of FS.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"921\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eoutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eexposure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003emethod\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003ensnp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003epval\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eor_lci95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eor_uci95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eorDrug\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eor_lci95Drug\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eor_uci95Drug\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eMR Egger\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.413071653715278\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.01619478056092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.978767240306829\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.05505353010746\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.984063310626353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.947819206763989\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.02169336980109\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eWeighted median\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.0559822803460556\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.03062224564626\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.999229702624722\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.06300104013207\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.97028761432657\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.940732851847219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.00077089119074\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eInverse variance weighted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.00424222419569982\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.04031775937388\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.01251182179604\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.06888731288976\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.96124476487055\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.935552314954958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.987642789420627\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSimple mode\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.0819905754456494\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.05821431826417\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.996386600028157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.12387856615861\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.944988158580523\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.889775844215959\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.00362650398123\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eWeighted mode\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.0637368823733314\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.03401745061736\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.00026402656448\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.06890986758115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.967101666807413\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.935532574194415\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.999736043127146\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eMR Egger\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.392694046606961\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.01526479709541\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.981302396033404\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.05040262042333\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.984964713502253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.952015903765536\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.01905386559961\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eWeighted median\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.0477303130724897\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.03052632923893\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.00030019607459\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.06166580734678\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.970377924005613\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.941915990022424\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.999699894016053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eInverse variance weighted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.00363342762514621\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.03158192849035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.01019047457168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.05342636064655\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.969384953712243\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.949283250692759\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.989912323637773\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSimple mode\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.174923223945707\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.0354603344021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.98622042173187\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.08715869241209\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.965754038832806\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.91982891456379\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.01397210802422\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eWeighted mode\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.0752122153095228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.03021864792613\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.998526503993596\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.06291666599724\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.970667733507867\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.940807527052735\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.00147567040085\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eMR Egger\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.656294955530936\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.01181436581668\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.961678129492346\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.06456441035365\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.988323583637649\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.939351334944402\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.03984895708077\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eWeighted median\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.163976241971478\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.0275444108972\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.988969025331487\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.06762445468115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.973193946066866\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.936658949329383\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.01115401431791\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eInverse variance weighted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.035206769263585\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.03070915846205\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.00209872764253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.06013643170347\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.970205796455842\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.943274818311032\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.997905667790375\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSimple mode\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.0834531468354106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.05475151834128\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.996302132106538\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.1166299153561\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.948090600118425\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.895551862123533\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.00371159287358\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eADAMTS-13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eWeighted mode\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.287172194396276\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.02741971881872\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.978937193745352\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.07830337366069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.973312057072207\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.927382798224155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.02151599345619\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;II Heterogeneity and pleiotropy tests.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eexposure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eoutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003emethod\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ_pval\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003eegger_intercept\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003ese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003epval\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eADAMTS-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003eMR Egger\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.333402403452115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.0128291316407622\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.00760262681657752\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0.109775221998388\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eADAMTS-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003eInverse variance weighted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.228281467427927\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eADAMTS-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003eMR Egger\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.470058079490945\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.00713386669190691\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.00613368931737666\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0.257850254616823\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eADAMTS-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003eInverse variance weighted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.449693027779464\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eADAMTS-13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003eMR Egger\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.990022301183422\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.00678442727509325\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.00791589612503133\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0.403330433055831\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eADAMTS-13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003eInverse variance weighted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.988893246270022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-orthopaedic-surgery-and-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"josr","sideBox":"Learn more about [Journal of Orthopaedic Surgery and Research](http://josr-online.biomedcentral.com)","snPcode":"13018","submissionUrl":"https://submission.nature.com/new-submission/13018/3","title":"Journal of Orthopaedic Surgery and Research","twitterHandle":"@MSKmedBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Mendelian randomization, Frozen shoulder, Pathogenesis, Inflammation, Fibrosis","lastPublishedDoi":"10.21203/rs.3.rs-6401117/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6401117/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eFrozen shoulder (FS) is a condition that causes shoulder pain and restricted movement, primarily due to inflammation, fibrosis, and adhesion of the shoulder joint capsule. It commonly affects individuals aged 30 to 60 years. Factors such as diabetes, obesity, and shoulder trauma are known risk factors. Although current treatments include nonsteroidal anti-inflammatory drugs, steroid injections, and physical therapy, approximately 22.5% of patients do not respond well to conservative treatments and may require surgical intervention. The ADAMTS family is thought to play a significant role in joint diseases, and this study investigates its impact on FS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study employed the Mendelian Randomization (MR) analysis method using genome-wide association studies (GWAS) data to analyze the causal relationships between the ADAMTS-5 and ADAMTS-13 genes and FS. By screening SNPs related to ADAMTS-1, ADAMTS-5, and ADAMTS-13, data analysis was performed using R software to verify the impact of these genes on FS pathogenesis. Additionally, co-location analysis was conducted to identify potential therapeutic targets.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe MR analysis results indicate that ADAMTS-1-mediated ADAMTS-5 levels, along with the levels of ADAMTS-5 and ADAMTS-13 themselves, significantly increase the risk of FS. Co-expression localization analysis revealed that rs62217270, rs977151, and rs4962153 are potential targets for inhibiting ADAMTS-1, ADAMTS-5, and ADAMTS-13, respectively.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study demonstrates that increased activity of the ADAMTS family may exacerbate the pathological changes in FS, and targeting the inhibition of these genes could offer a new direction for FS intervention. This research provides potential targeted therapeutic approaches for FS treatment and lays the foundation for future clinical studies.\u003c/p\u003e","manuscriptTitle":"ADAMTS-1, ADAMTS-5 and ADAMTS-13 are considered potential targets in the treatment of frozen shoulder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-16 09:13:24","doi":"10.21203/rs.3.rs-6401117/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-08T12:23:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-07T18:40:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"57923579832166247184934533606120014068","date":"2025-04-23T02:57:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321410973343325130269019019682172453170","date":"2025-04-22T19:39:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-21T13:58:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"86278018762606590029362427328753758285","date":"2025-04-21T13:05:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-14T09:07:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"158671351833946120247659917534595001132","date":"2025-04-09T02:59:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-09T01:41:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-08T09:24:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-08T08:56:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Orthopaedic Surgery and Research","date":"2025-04-08T08:28:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-orthopaedic-surgery-and-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"josr","sideBox":"Learn more about [Journal of Orthopaedic Surgery and Research](http://josr-online.biomedcentral.com)","snPcode":"13018","submissionUrl":"https://submission.nature.com/new-submission/13018/3","title":"Journal of Orthopaedic Surgery and Research","twitterHandle":"@MSKmedBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"95ccba68-1429-4bd3-98cb-2a15b71835ee","owner":[],"postedDate":"April 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-24T16:07:14+00:00","versionOfRecord":{"articleIdentity":"rs-6401117","link":"https://doi.org/10.1186/s13018-025-06002-9","journal":{"identity":"journal-of-orthopaedic-surgery-and-research","isVorOnly":false,"title":"Journal of Orthopaedic Surgery and Research"},"publishedOn":"2025-11-18 15:58:34","publishedOnDateReadable":"November 18th, 2025"},"versionCreatedAt":"2025-04-16 09:13:24","video":"","vorDoi":"10.1186/s13018-025-06002-9","vorDoiUrl":"https://doi.org/10.1186/s13018-025-06002-9","workflowStages":[]},"version":"v1","identity":"rs-6401117","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6401117","identity":"rs-6401117","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}