The inhibition of bone morphogenetic protein 1 attenuates endometriosis lesions in vivo and in vitro

Purpose To investigate the potential role of Bone morphogenetic protein 1 (BMP1) in endometriosis lesions.

Endometriosis model in mice was established. The expression of BMP1-3 expression in mice of endometriosis lesions was evaluated. The effect of the treatment with anti-BMP1 antibodies on the expression of MMP2, MMP9, TGF-β, IL-17, IL-1β, Col1a1 and Col1a2 levels in mice was evaluated. In endometriosis cell model, the expression of IL-17, IL-1β, MMP2 and MMP9 levels and MIF, YWHAZ, β-catenin and CAP39 mRNA levels was also detected.

The expression of BMP1-3 expression was upregulated in mice of endometriosis lesions (p < 0.01). Treatment with anti-BMP1 antibodies dose-dependently reduced MMP2, MMP9, TGF-β, IL-17, IL-1β, Col1a1 and Col1a2 levels in mice (p < 0.01). Treatment with anti-BMP1 antibodies suppressed TGF-β/PI3K/Akt signaling pathway. In vitro cell, si-BMP1 suppressed TGF-β/PI3K/Akt signaling pathway.

The data support the hypothesis that the inhibition of BMP1 is involved in the pathogenesis of endometriosis lesions. Similar content being viewed by others

Yang Y, Zhu W, Chen S, Zhang G, Chen M, Zhuang Y (2019) Laparoscopic surgery combined with GnRH agonist in endometriosis. J Coll Phys Surg Pak 29:313–316 Thabet AAE, Alshehri MA (2018) Effect of pulsed high-intensity laser therapy on pain, adhesions, and quality of life in women having endometriosis: a randomized controlled trial. Photomed Laser Surg 36:363–369 Bourdon M, Raad J, Dahan Y, Marcellin L, Maignien C, Even M, Pocate-Cheriet K, Lamau MC, Santulli P, Chapron C (2018) Endometriosis and ART: a prior history of surgery for OMA is associated with a poor ovarian response to hyperstimulation. PLoS ONE 13:e0202399 Bai M, Lei J, Wang S, Ding D, Yu X, Guo Y, Chen S, Du Y, Li D, Zhang Y, Huang S, Jia Z, Zhang A (2019) BMP1 inhibitor UK-383,367 attenuates renal fibrosis and inflammation in CKD. Am J Physiol Renal Physiol 317(6):F1430–F1438 Luo X, Chen L, Huang Q, Zheng J, Zhou W, Peng D, Ruan L, Sun M (2013) Bacillus thuringiensis metalloproteinase Bmp1 functions as a nematicidal virulence factor. Appl Environ Microbiol 79:460–468 Zhu Q, Guo W, Zhang S, Feng Y, Wang X, Greenspan DS, Zhou L, Huang GR (2019) Synergistic effect of PCPE1 and sFRP2 on the processing of procollagens via BMP1. FEBS Lett 593:760 Xiao W, Wang X, Wang, Xing J (2019) Overexpression of BMP1 reflects poor prognosis in clear cell renal cell carcinoma. Cancer Gene Ther. Ibrahim MG, Elghonaimy EA, Schafer S, Vennemann M, Kliesch S, Kiesel L, Götte M, Schüring AN (2019) Seminal plasma (SP) induces a rapid transforming growth factor beta 1 (TGFbeta1)-independent up-regulation of epithelial–mesenchymal transdifferentiation (EMT) and myofibroblastic metaplasia-markers in endometriotic (EM) and endometrial cells. Arch Gynecol Obstet 299:173–183 Zhou Y, Zeng C, Li X, Wu PL, Yin L, Yu XL, Zhou YF, Xue Q (2016) IGF-I stimulates ERbeta and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis. J Mol Med (Berl) 94:887–897 Madanes D, Bilotas MA, Baston JI, Singla JJ, Meresman GF, Barañao RI, Ricci AG (2019) PI3K/AKT pathway is altered in the endometriosis patient's endometrium and presents differences according to severity stage. Gynecol Endocrinol 36:1–5 Voloshenyuk TG, Landesman ES, Khoutorova E, Hart AD, Gardner JD (2011) Induction of cardiac fibroblast lysyl oxidase by TGF-β1 requires PI3K/Akt, Smad3, and MAPK signaling. Cytokine 55(1):90–97 Griffith JS, Binkley PA, Kirma NB, Schenken RS, Witz CA, Tekmal RR (2010) Imatinib decreases endometrial stromal cell transmesothial migration and proliferation in the extracellular matrix of modeled peritoneum. Fertil Steril 94(7):2531–2535 Cao Y, Ye Q, Zhuang M, Xie S, Zhong R, Cui J, Zhou J, Zhu Y, Zhang T, Cao L (2017) Ginsenoside Rg3 inhibits angiogenesis in a rat model of endometriosis through the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway. PLoS ONE 12:e0186520 Somigliana E, Viganò P, Rossi G, Carinelli S, Vignali M, Panina-Bordignon P (1999) Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis. Hum Reprod 14(12):2944–2950 Borrelli GM, Kaufmann AM, Abrao MS, Mechsner S (2015) Addition of MCP-1 and MIP-3beta to the IL-8 appraisal in peritoneal fluid enhances the probability of identifying women with endometriosis. J Reprod Immunol 109:66–73 El-Kasti MM, Wright C, Fye HK, Roseman F, Kessler BM, Becker CM (2011) Urinary peptide profiling identifies a panel of putative biomarkers for diagnosing and staging endometriosis. Fertil Steril 95(1261–1266):e1261–1266 Yeung P Jr, Sinervo K, Winer W, Albee RB Jr (1912e) Complete laparoscopic excision of endometriosis in teenagers: is postoperative hormonal suppression necessary? Fertil Steril 95(1909–1912):1912e1901 Ibrahim MG, Sillem M, Plendl J, Taube ET, Schüring A, Götte M, Chiantera V, Sehouli J, Mechsner S (2019) Arrangement of myofibroblastic and smooth muscle-like cells in superficial peritoneal endometriosis and a possible role of transforming growth factor beta 1 (TGFbeta1) in myofibroblastic metaplasia. Arch Gynecol Obstet 299:489–499 Young VJ, Ahmad SF, Brown JK, Duncan WC, Horne AW (2015) Peritoneal VEGF-A expression is regulated by TGF-beta1 through an ID1 pathway in women with endometriosis. Sci Rep 5:16859 Ge G, Greenspan DS (2006) BMP1 controls TGFbeta1 activation via cleavage of latent TGFbeta-binding protein. J Cell Biol 175:111–120 Zhou A, Hong Y, Lv Y (2019) Sulforaphane attenuates endometriosis in rat models through inhibiting PI3K/Akt signaling pathway. Dose Response 17:1559325819855538 Takeuchi A, Koga K, Satake E, Makabe T, Taguchi A, Miyashita M, Takamura M, Harada M, Hirata T, Hirota Y, Yoshino O, Wada-Hiraike O, Fujii T, Osuga Y (2019) Endometriosis triggers excessive activation of primordial follicles via PI3K-PTEN-Akt-Foxo3 pathway. J Clin Endocrinol Metab 104:5547–5554 Diao R, Wei W, Zhao J, Tian F, Cai X, Duan YG (2017) CCL19/CCR7 contributes to the pathogenesis of endometriosis via PI3K/Akt pathway by regulating the proliferation and invasion of ESCs. Am J Reprod Immunol 78(5). Liu Y, Qin X, Lu X, Jiang J (2019) Effects of inhibiting the PI3K/Akt/mTOR signaling pathway on the pain of sciatic endometriosis in a rat model. Can J Physiol Pharmacol 97:963–970 Saito A, Osuga Y, Yoshino O, Takamura M, Hirata T, Hirota Y, Koga K, Harada M, Takemura Y, Yano T, Taketani Y (2011) TGF-beta1 induces proteinase-activated receptor 2 (PAR2) expression in endometriotic stromal cells and stimulates PAR2 activation-induced secretion of IL-6. Hum Reprod 26:1892–1898 Funding N/A. Author information Authors and Affiliations Contributions WW carried out the study concepts; XH, WW were dedicated to the study design, literature research and manuscript review; XH was involved in the definition of intellectual content, experimental studies, data analysis, manuscript preparation and manuscript editing; XH and FH were dedicated to clinical studies; XH, FH and FC carried out the data acquisition; FH and FC were involved in the statistical analysis. All authors have read and approved this article. Corresponding author Ethics declarations Conflict of interest The authors declare that they have no competing interest. Ethical statement This study was carried out in accordance with recommendations of the regulations for animal experimentation in Hyogo College of Medicine of The University of Hong Kong-Shenzhen Hospital. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions About this article Cite this article Han, X., Hu, F., Chen, F. et al. The inhibition of bone morphogenetic protein 1 attenuates endometriosis lesions in vivo and in vitro. Arch Gynecol Obstet 302, 415–422 (2020). https://doi.org/10.1007/s00404-020-05612-4 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s00404-020-05612-4