Abstract
Osteoarthritis (OA) results from an imbalance of the dynamic equilibrium between the breakdown and repair of joint tissues. Previously, we reported that Runx1 enhanced chondrogenic differentiation through transcriptional induction of COL2A1, and suppressed hypertrophic differentiation. Here, we investigated the involvement of Runx1 in OA development as well as its potential underlying molecular mechanism. When we analysed OA development in Col2a1-Cre;Runx1fl/fl and Runx1fl/fl mice by surgically inducing joint instability, Cartilage degradation and osteophyte formation of Col2a1-Cre;Runx1fl/fl joints was accelerated compared with joints in Runx1fl/fl animals 8 weeks after surgery. To investigate chondrocyte regulation by Runx1, we analysed interactions with co-factors and downstream molecules. Runx1 enhanced cartilage matrix production in cooperation with Sox5, Sox6, and Sox9, and co-immunoprecipitation assays showed protein–protein binding between Runx1 and each Sox protein. Knockdown of Runx1 increased expression of a hypertrophic marker, Co10a1, in mouse articular cartilage and primary chondrocytes. This expression was accompanied by decreased expression of Bapx1, a potent suppressor of hypertrophic differentiation. Notably, Runx1-induced suppression of hypertrophic differentiation was diminished by siRNA silencing of Bapx1, whereas chondrogenic markers were unaltered. Thus, Runx1 contributes to articular cartilage maintenance by enhancing matrix production in cooperation with Sox proteins, and suppressing hypertrophic differentiation at least partly via Bapx1 induction.
Highlights
Development of osteoarthritis (OA) – the most common degenerative joint disorder – results from an imbalance in the dynamic equilibrium between breakdown and repair of joint tissues, and ectopic endochondral ossification under mechanical loading conditions[1,2]
No abnormalities were found in skeletal morphology or patterning, chondrocyte-specific Runx[1] knockout mice (Col2a1-Cre;Runx1fl/fl), showed slight dwarfism compared with their Runx1fl/fl littermates at 8 weeks of age (Fig. 1a)
sex determining region Y-box (Sox)[5], Sox[6], and Sox[9] are bona fide transcription factors that are indispensable for chondrogenesis[20]
Summary
Development of osteoarthritis (OA) – the most common degenerative joint disorder – results from an imbalance in the dynamic equilibrium between breakdown and repair of joint tissues, and ectopic endochondral ossification under mechanical loading conditions[1,2] During this process, chondrocytes undergo hypertrophic differentiation characterized by secretion of type X collagen (Col10a1). We recently showed that intraarticular injection of polyplex nanomicelles containing RUNX1 mRNA suppressed development of surgically-induced OA in mice[16] These data support a protective role of Runx[1] with regard to articular cartilage maintenance; molecular mechanisms underlying enhancement of cartilage matrix production and suppression of hypertrophic differentiation by Runx[1] are not well understood. We further examined interactions between Runx[1] and other chondrogenic factors in enhancement of cartilage matrix production, as well as the function of molecules downstream of Runx[1] in regulation of hypertrophic differentiation
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