Abstract
SummaryObjectiveThe matricellular protein NOV/CCN3, is implicated in osteoarthritis (OA) and targeted mutation of NOV in mice (Novdel3) leads to joint abnormalities. This investigation tested whether NOV is required for joint homeostasis and if its disruption causes joint degeneration.MethodNOV expression in the adult mouse joint was characterized by immunohistochemistry. A detailed comparison of the joints of Novdel3−/− and Novdel3+/+ (wild-type) males and females at 2, 6 and 12 months of age was determined by X-ray, histology and immunohistochemistry.ResultsNOV protein was found in specific cells in articular cartilage, meniscus, synovium and ligament attachment sites in adult knees. Novdel3−/− males exhibited severe OA-like pathology at 12 months (OARSI score 5.0 ± 0.5, P < 0.001), affecting all tissues of the joint: erosion of the articular cartilage, meniscal enlargement, osteophytic outgrowths, ligament degeneration and expansion of fibrocartilage. Subchondral sclerosis and changes in extracellular matrix composition consistent with OA, were also seen. The density of articular cartilage cells in Novdel3+/+ knee joints is maintained at a constant level from 2 to 12 months of age whereas this is not the case in Novdel3−/− mice. Compared with age and sex-matched Novdel3+/+ mice, a significant increase in articular cartilage density was seen in Novdel3−/− males at 2 months, whereas a significant decrease was seen at 6 and 12 months in both Novdel3−/− males and females.ConclusionNOV is required for the maintenance of articular cartilage and for joint homeostasis, with disruption of NOV in ageing Novdel3−/− male mice causing OA-like disease.
Highlights
An impaired ability to maintain homeostasis of the joint is associated with tissue degeneration, yet the mechanisms that regulate this process are largely unknown
Homeostasis of articular cartilage is crucial to joint health
We show that the density of articular cartilage cells is normally maintained at a constant level in adult 129Sv mice between 2 and 12 months of age, whereas, this homeostatic process is compromised in Novdel3À/À mutants
Summary
An impaired ability to maintain homeostasis of the joint is associated with tissue degeneration, yet the mechanisms that regulate this process are largely unknown. The association of OA with impaired joint homeostasis suggests common regulators in the pathways mediating these processes. NOV (CCN3) is a member of the CCN family of matricellular proteins which have important roles in development, wound healing, angiogenesis and disease. In skeletal development and disease CTGF (CCN2) is required for coordinating chondrogenesis and angiogenesis[2], WISP1 (CCN4) is upregulated in OA3 and mutations in WISP3 (CCN6) cause progressive pseudorheumatoid dysplasia[4], while NOV (CCN3) has roles in skeletal development[5], regulation of osteogenesis[6,7], bone regeneration[8] and bone cancer[9]. By specific interactions with these domains, CCN proteins modulate multiple signalling pathways including BMPs, Wnt, TGFs, Notch and integrins to regulate cell proliferation, survival, adhesion, migration and differentiation[10]
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