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Insulin\u2010like growth factor\u2010binding protein 3 (IGFBP3) is highly expressed in the endometrium and at the maternal\u2010fetal interface in multiple species, including humans. BMP2\u2010induced IGFBP3 signaling has been confirmed to have a role in trophoblast cell invasion; however, the involvement of this signaling pathway in endometrial remodeling remains poorly understood. To determine the roles of BMP2 in regulating IGFBP3 expression during the transformation of endometrial stromal cells, we employed immortalized human endometrial stromal cells (HESCs) and primary human decidual stromal cells (HDSCs) as study models. We showed that BMP2 significantly increased the expression of IGFBP3 in a dose\u2010 and time\u2010dependent manner in both HESCs and primary HDSCs. Additionally, the BMP2\u2010induced upregulation of IGFBP3 is mediated by the inhibitor of DNA\u2010binding 1 (ID1), and knockdown of ALK3 completely abolished BMP2\u2010induced upregulation of ID1. Moreover, BMP2 increased the expression of matrix metalloproteinases 2 (MMP2) and promoted cell migration in HESCs and primary HDSCs. Knockdown of either IGFBP3 or ID1 significantly suppressed the basal and the BMP2\u2010induced increase in MMP2 expression as well as the cell migration in both cell models. These data demonstrated that BMP2 upregulated the expression of ID1, which in turn induced the expression of IGFBP3, and these BMP2\u2010induced cell activities were most likely mediated by the ALK3 type I receptor. The increased expression of IGFBP3 promoted the MMP2 expression and cell migration in both HESCs and HDSCs. These findings deepen our understanding of a newly identified mechanism by which BMP2 and IGFBP3 regulate endometrial remodeling in humans, which provides insight into potential therapies for endometrium\u2010related diseases and pregnancy\u2010induced complications.<\/jats:p>","DOI":"10.1096\/fj.202000508r","type":"journal-article","created":{"date-parts":[[2020,9,25]],"date-time":"2020-09-25T06:16:51Z","timestamp":1601014611000},"page":"15462-15479","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["The regulation of IGFBP3 by BMP2 has a role in human endometrial remodeling"],"prefix":"10.1096","volume":"34","author":[{"given":"Jin","family":"Luo","sequence":"first","affiliation":[{"name":"Reproductive Medicine Center Renmin Hospital of Wuhan University Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development Wuhan China"},{"name":"Department of Obstetrics and Gynaecology BC Children\u2019s Hospital Research Institute University of British Columbia Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology BC Children\u2019s Hospital Research Institute University of British Columbia Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsun\u2010Ming","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology BC Children\u2019s Hospital Research Institute University of British Columbia Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung\u2010Ming","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology BC Children\u2019s Hospital Research Institute University of British Columbia Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center Renmin Hospital of Wuhan University Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C. 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