Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia

Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia | 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 Article Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia I-Ping Chen, Yasuyuki Fujii, Iichiro Okabe, Ayano Hatori, Shyam Sah, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3906170/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Craniometaphyseal dysplasia (CMD), a rare craniotubular disorder, occurs in an autosomal dominant (AD) or autosomal recessive (AR) form. CMD is characterized by hyperostosis of craniofacial bones and flaring metaphyses of long bones. Many patients with CMD suffer from neurological symptoms. To date, the pathogenesis of CMD is not fully understood. Treatment is limited to decompression surgery. Here, we report a knock in (KI) mouse model for AR CMD carrying a R239Q mutation in CX43. Cx43 KI/KI mice replicate many features of AR CMD in craniofacial and long bones. In contrast to Cx43 +/+ littermates, Cx43 KI/KI mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones, leading to an expanded bone marrow cavity and increased cortical bone thickness. Although formation of Cx43 +/+ and Cx43 KI/KI resting OCs are comparable, on bone chips the actively resorbing Cx43 KI/KI OCs resorb less bone. Cortical bones of Cx43 KI/KI mice have an increase in degenerating osteocytes and empty lacunae. Osteocyte dendrite formation is decreased with reduced expression levels of Fgf23 , Sost , Tnf-α , IL-1β , Esr1 , Esr2 , and a lower Rankl/Opg ratio. Female Cx43 KI/KI mice display a more severe phenotype. Sexual dimorphism in bone becomes more evident as mice age. Our data show that the CX43R239Q mutation results in mislocalization of CX43 protein and impairment of gap junction and hemichannel activity. Different from CX43 ablation mouse models, the CX43R239Q mutation leads to the AR CMD-like phenotype in Cx43 KI/KI mice not only by loss-of-function but also via a not yet revealed dominant function. Health sciences/Pathogenesis Health sciences/Diseases Genetic animal models Bone μCT Bone histomorphometry Osteocytes Osteoclasts Full Text Additional Declarations (Not answered) Supplementary Files Supplefile20240126.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 20 Mar, 2024 Review # 3 received at journal 19 Mar, 2024 Review # 2 received at journal 06 Mar, 2024 Reviewer # 3 agreed at journal 05 Mar, 2024 Reviewer # 2 agreed at journal 22 Feb, 2024 Review # 1 received at journal 17 Feb, 2024 Reviewer # 1 agreed at journal 07 Feb, 2024 Reviewers invited by journal 03 Feb, 2024 Submission checks completed at journal 31 Jan, 2024 Editor assigned by journal 28 Jan, 2024 First submitted to journal 28 Jan, 2024 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-3906170","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":270890228,"identity":"18228266-ec59-4358-b73d-02a11490decd","order_by":0,"name":"I-Ping 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AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Genetic animal models, Bone μCT, Bone histomorphometry, Osteocytes, Osteoclasts","lastPublishedDoi":"10.21203/rs.3.rs-3906170/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3906170/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Craniometaphyseal dysplasia (CMD), a rare craniotubular disorder, occurs in an autosomal dominant (AD) or autosomal recessive (AR) form. CMD is characterized by hyperostosis of craniofacial bones and flaring metaphyses of long bones. Many patients with CMD suffer from neurological symptoms. To date, the pathogenesis of CMD is not fully understood. Treatment is limited to decompression surgery. Here, we report a knock in (KI) mouse model for AR CMD carrying a R239Q mutation in CX43. \u003ci\u003eCx43\u003csup\u003eKI/KI\u003c/sup\u003e\u003c/i\u003e mice replicate many features of AR CMD in craniofacial and long bones. In contrast to \u003ci\u003eCx43\u003csup\u003e+/+\u003c/sup\u003e\u003c/i\u003e littermates, \u003ci\u003eCx43\u003csup\u003eKI/KI\u003c/sup\u003e\u003c/i\u003e mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones, leading to an expanded bone marrow cavity and increased cortical bone thickness. Although formation of \u003ci\u003eCx43\u003csup\u003e+/+\u003c/sup\u003e\u003c/i\u003e and \u003ci\u003eCx43\u003csup\u003eKI/KI\u003c/sup\u003e\u003c/i\u003e resting OCs are comparable, on bone chips the actively resorbing \u003ci\u003eCx43\u003csup\u003eKI/KI\u003c/sup\u003e\u003c/i\u003e OCs resorb less bone. Cortical bones of \u003ci\u003eCx43\u003csup\u003eKI/KI\u003c/sup\u003e\u003c/i\u003e mice have an increase in degenerating osteocytes and empty lacunae. Osteocyte dendrite formation is decreased with reduced expression levels of \u003ci\u003eFgf23\u003c/i\u003e, \u003ci\u003eSost\u003c/i\u003e, \u003ci\u003eTnf-α\u003c/i\u003e, \u003ci\u003eIL-1β\u003c/i\u003e, \u003ci\u003eEsr1\u003c/i\u003e, \u003ci\u003eEsr2\u003c/i\u003e, and a lower \u003ci\u003eRankl/Opg\u003c/i\u003e ratio. Female \u003ci\u003eCx43\u003csup\u003eKI/KI\u003c/sup\u003e\u003c/i\u003e mice display a more severe phenotype. Sexual dimorphism in bone becomes more evident as mice age. Our data show that the CX43R239Q mutation results in mislocalization of CX43 protein and impairment of gap junction and hemichannel activity. Different from CX43 ablation mouse models, the CX43R239Q mutation leads to the AR CMD-like phenotype in \u003ci\u003eCx43\u003csup\u003eKI/KI\u003c/sup\u003e\u003c/i\u003e mice not only by loss-of-function but also via a not yet revealed dominant function.","manuscriptTitle":"Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-06 03:25:10","doi":"10.21203/rs.3.rs-3906170/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-03-21T02:51:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-03-19T04:33:12+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-03-06T18:55:20+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-03-05T15:33:12+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-02-22T22:10:48+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-02-17T23:03:47+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-02-07T13:39:32+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-02-04T03:34:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-01T01:53:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-28T15:20:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Research","date":"2024-01-28T15:20:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-research","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"boneres","sideBox":"Learn more about [Bone Research](http://www.nature.com/boneres/)","snPcode":"41413","submissionUrl":"https://mts-boneres.nature.com/cgi-bin/main.plex","title":"Bone Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0fb59ae8-d8c2-4644-aadc-6eaf7169307c","owner":[],"postedDate":"February 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":28553484,"name":"Health sciences/Pathogenesis"},{"id":28553485,"name":"Health sciences/Diseases"}],"tags":[],"updatedAt":"2024-10-15T06:07:11+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-06 03:25:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3906170","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3906170","identity":"rs-3906170","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}