Depletion of collagen IX alpha2 interferes osteochondral homeostasis of the knee joint which ultimately causing osteoarthritis-like articular cartilage damage

Abstract

As one of the branched chains of Type IX collagen (Col9), Collagen IX alpha2 (Col92) has been reported to be associated with several orthopedic conditions. To probe the relationship between Col92 and knee osteoarthritis (KOA), we performed a systematic analysis of Col92-deficient (Col9-/-) mice using whole-mount skeletal staining, Micro-CT (CT), biomechanics, histomorphometry, immunohistochemistry (IHC), immunofluorescence (IF) and Enzyme-linked immunosorbent (Elisa). Although whole-mount skeletal staining displayed no difference in bone length and ossification between Col9-/- mice and wild-type (Col92+/+) mice at mid-gestation and adult stages, the knee joint exhibited dramatic discrepancies. Specifically, the subchondral bone (SCB) in the knee joint of Col9-/- mice became sparse and deformed in the early stage, with altered bone morphometric parameters, reduced load-bearing capacity, dysfunctional bone homeostasis (decreased osteogenesis capacity and elevated bone resorption capacity), diminished cartilage proteoglycans and disrupted cartilage extracellular matrix (ECM) anabolism and catabolism compared with the Col92+/+ mice. In the late stage, the cartilage degeneration in Col92-/- mice were particularly pronounced compared to Col92+/+ mice, as evidenced by severe cartilage destruction and a marked reduction in cartilage thickness and area. Overall, Col92 is essential for maintaining osteochondral homeostasis in the knee joint of mice, and the absence of this gene is accompanied by distinct sclerosis of the SCB and a reduction in load-bearing capacity; in the late stage, in the lack of SCB stress inhibition, excessive load is consistently exerted on the cartilage, ultimately leading to osteoarthritic-like articular cartilage damage. Hence, Col92 may serve as a potential candidate biomarker associated with KOA.