Enhanced BMP signalling causes growth plate cartilage dysrepair in rats

Yu-Wen Su; Derick S K Wong; Jian Fan; Rosa Chung; Liping Wang; Yuhui Chen; Claire H Xian; Lufeng Yao; Liang Wang; Bruce K Foster; Jiake Xu; Cory J Xian

doi:10.1016/j.bone.2021.115874

Enhanced BMP signalling causes growth plate cartilage dysrepair in rats

Bone. 2021 Apr:145:115874. doi: 10.1016/j.bone.2021.115874. Epub 2021 Feb 4.

Authors

Yu-Wen Su¹, Derick S K Wong¹, Jian Fan², Rosa Chung¹, Liping Wang³, Yuhui Chen⁴, Claire H Xian⁵, Lufeng Yao⁶, Liang Wang⁴, Bruce K Foster⁷, Jiake Xu⁸, Cory J Xian⁹

Affiliations

¹ University of South Australia, UniSA Clinical and Health Sciences, Adelaide, SA 5001, Australia.
² Department of Orthopedics, Tongji Hospital, Tongji University, Shanghai 200065, China.
³ University of South Australia, UniSA Clinical and Health Sciences, Adelaide, SA 5001, Australia; Ningbo No. 6 Hospital, Ningbo University, Ningbo 315040, China.
⁴ Department of Orthopedics, Orthopaedic Hospital of Guangdong Province, the Third Affiliated Hospital of Southern Medical University, Academy of Orthopaedics of Guangdong Province, Guangzhou 510630, Guangdong, China.
⁵ Discipline of Physiology, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia.
⁶ Ningbo No. 6 Hospital, Ningbo University, Ningbo 315040, China.
⁷ Department of Orthopaedic Surgery, Flinders Medical Centre, Bedford Park, SA 5042, Australia.
⁸ School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA 6009, Australia.
⁹ University of South Australia, UniSA Clinical and Health Sciences, Adelaide, SA 5001, Australia; Department of Orthopedics, Tongji Hospital, Tongji University, Shanghai 200065, China; Ningbo No. 6 Hospital, Ningbo University, Ningbo 315040, China. Electronic address: cory.xian@unisa.edu.au.

PMID: 33548573
DOI: 10.1016/j.bone.2021.115874

Abstract

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.

Keywords: BMP signalling; BMPs; Bone growth defects; Cartilage degeneration; Growth plate; Injury repair.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cartilage
Growth Plate*
Osteogenesis
Rats
Rats, Sprague-Dawley
Salter-Harris Fractures*