{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:58:45Z","timestamp":1790827125469,"version":"4.1.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"\n Introduction<\/jats:title>\n Atrophic non-union is a significant clinical challenge associated with impaired early inflammation resolution and delayed osteogenesis. Although the osteoimmune microenvironment is critical for bone healing, the specific molecular mechanisms regulating this process require further elucidation.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We utilized a 6-mm critical-size rat femoral defect model and time-series RNA sequencing to explore potential molecular mechanisms. Additionally, primary mouse bone marrow-derived macrophages (BMMs) were used for in vitro validation of in vivo findings.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Histological and transcriptomic analyses identified 1-2 weeks post-fracture as a critical window characterized by significant inhibition of the canonical BMP9-SMAD signaling cascade in the non-union microenvironment.\n In vivo<\/jats:italic>\n , this defect was associated with sustained accumulation of M1 macrophages, impaired reparative M2 polarization, and osteoclast-mediated bone resorption.\n In vitro<\/jats:italic>\n studies further validated the in vivo results, confirming that BMP9 promotes M2 macrophage polarization, upregulates chemokines Ccl2 and Ccl7, and inhibits RANKL-induced osteoclastogenesis through the canonical SMAD-ID1 pathway.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n Early loss of canonical BMP9-SMAD signaling disrupts the balance between immune cell recruitment and bone remodeling, contributing to the development of atrophic non-union in critical-size defects. Targeted modulation of the BMP9-driven osteoimmune axis may offer a potential therapeutic strategy for impaired bone healing.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fendo.2026.1815554","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:20:40Z","timestamp":1784521240000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Deficient early canonical BMP9-SMAD signaling and dysregulated macrophage microenvironment characterize the failure of bone healing in a critical-size defect model"],"prefix":"10.3389","volume":"17","author":[{"given":"Kai","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]},{"name":"Functional Validation Platform for Pathogenic Genes in Pediatric Rare Diseases, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Radiology Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengyi","family":"Huang","sequence":"additional","affiliation":[{"name":"Functional Validation Platform for Pathogenic Genes in Pediatric Rare Diseases, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development 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