Purpose: To investigate the roles of osteomodulin (OMD), a small proteoglycan known for controlling collagen fibrils organization in bone, in the development of osteoarthritis (OA) associated with subchondral bone sclerosis.
Methods: Loss of function and overexpressing mice for Omd aged 4, 8, and 16 months were used to study Omd roles in bone and cartilage metabolism and answer whether mice develop spontaneous OA. Surgical destabilization of the medial meniscus (DMM) model was performed to investigate its role in mechanically-induced OA. Additionally, we used omd overexpression as well as a mutant deficiency for omd in the zebrafish model to study omd effects on skeletal metabolism and cartilage development. Finally, in vitro models were used to further study OMD in osteoclastogenesis.
Results: Omd regulated bone and cartilage microarchitectures. Knock-out mice showed thinner calcified cartilage in the medial tibial plateau, and their growth plate was thicker at 16 months compared to WT. Both trabecular and cortical bone volume/total volume ratios were increased in the Omd knock-out mice and they showed a reduced percentage of porosity. The trabecular number of the knock-out mice was increased while their trabecular total volume was decreased. Further, their cortical bone showed increased thickness, and a higher whole bone strength. Knock-out mice were more prone to develop cartilage lesions spontaneously. Interestingly, Omd knock-out mice developed subchondral bone sclerosis spontaneously while overexpressing mice showed less subchondral bone sclerosis in the DMM OA model. At 16 months, Omd-overexpressing mice had the less trabecular number and a greater structure-model index for their trabecular bone geometry. The zebrafish model showed that the ectopic overexpression of omd induced developmental defects with abnormal cartilage structures. Further, we studied the development of OA in zebrafish, an animal model that develop OA features in the synovial jaw joint during aging and which is an excellent genetic model to study OA. We showed that adult zebrafish lacking omd were more prone to articular cartilage degeneration. Furthermore, mutant zebrafish showed increased mature osteoclasts generation and increased TRAP staining revealing a higher osteoclast activity. Impaired osteoclastogenesis might be involved in the defects involved during scale regeneration. Our zebrafish results are supported by our in vitro experiments where we demonstrated that OMD bound to RANKL and inhibited osteoclastogenesis.
Conclusions: OMD is a key factor in subchondral bone sclerosis associated with OA. This small proteoglycan participates in bone and cartilage homeostasis notably by acting on the regulation of osteoclastogenesis.