Enhanced BMP signalling causes growth plate cartilage dysrepair in rats

• Published in: Bone (New York, N.Y.) Vol. 145; p. 115874
• Main Authors: Su, Yu-Wen, Wong, Derick S.K., Fan, Jian, Chung, Rosa, Wang, Liping, Chen, Yuhui, Xian, Claire H., Yao, Lufeng, Wang, Liang, Foster, Bruce K., Xu, Jiake, Xian, Cory J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021
• Subjects: BMP signalling; BMPs; Bone growth defects; Cartilage degeneration; Growth plate; Injury repair; BMP signalling; Growth plate; BMPs; Injury repair; Cartilage degeneration; Bone growth defects
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2021.115874

Growth plate cartilage injuries often result in bony repair at the injury site and premature mineralisation at the uninjured region causing bone growth defects, for which underlying mechanisms are unclear. With the prior microarray study showing upregulated bone morphogenetic protein (BMP) signalling during the injury site bony repair and with the known roles of BMP signalling in bone healing and growth plate endochondral ossification, this study used a rat tibial growth plate drill-hole injury model with or without systemic infusion of BMP antagonist noggin to investigate roles of BMP signalling in injury repair responses within the injury site and in the adjacent “uninjured” cartilage. At days 8, 14 and 35 post-injury, increased expression of BMP members and receptors and enhanced BMP signalling (increased levels of phosphorylated (p)-Smad1/5/8) were found during injury site bony repair. After noggin treatment, injury site bony repair at days 8 and 14 was reduced as shown by micro-CT and histological analyses and lower mRNA expression of osteogenesis-related genes Runx2 and osteocalcin (by RT-PCR). At the adjacent uninjured cartilage, the injury caused increases in the hypertrophic zone/proliferative zone height ratio and in mRNA expression of hypertrophy marker collagen-10, but a decrease in chondrogenesis marker Sox9 at days 14 and/or 35, which were accompanied by increased BMP signalling (increased levels of pSmad1/5/8 protein and BMP7, BMPR1a and target gene Dlx5 mRNA). Noggin treatment reduced the hypertrophic zone/proliferative zone height ratio and collagen-10 mRNA expression, but increased collagen-2 mRNA levels at the adjacent growth plate. This study has identified critical roles of BMP signalling in the injury site bony repair and in the hypertrophic degeneration of the adjacent growth plate in a growth plate drill-hole repair model. Moreover, suppressing BMP signalling can potentially attenuate the undesirable bony repair at injury site and suppress the premature hypertrophy but potentially rescue chondrogenesis at the adjacent growth plate. •Trauma injury often leads to dysrepair at the injured growth plate cartilage, for which molecular mechanisms are unclear.•BMP signalling was shown upregulated in a prior microarray study, but its function in growth plate repair is unclear.•Systemic treatment with BMP inhibitor noggin suppressed the bony repair at the growth plate injury site in rats.•Systemic BMP inhibitor noggin treatment attenuated premature hypertrophy at the adjacent uninjured growth plate cartilage.•Enhanced BMP signalling promotes injury site bony repair and premature hypertrophy at the uninjured growth plate cartilage.