Runx1 contributes to articular cartilage maintenance by enhancement of cartilage matrix production and suppression of hypertrophic differentiation
Runx1 contributes to articular cartilage maintenance by enhancement of cartilage matrix production and suppression of hypertrophic differentiation
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DOI：
10.1038/s41598-019-43948-3
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发表时间：
2019-05
影响因子：
4.6
通讯作者：
Fumiko Yano;Shinsuke Ohba;Yasutaka Murahashi;Sakae Tanaka;Taku Saito;U. Chung
中科院分区：
文献类型：
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作者：
Fumiko Yano;Shinsuke Ohba;Yasutaka Murahashi;Sakae Tanaka;Taku Saito;U. Chung
骨关节炎（OA）是由于关节组织的破坏和修复之间的动态平衡失衡而导致的。以前，我们报道Runx 1通过转录诱导COL 2A 1增强软骨分化，并抑制肥大分化。在这里，我们研究了Runx 1在OA发展中的参与及其潜在的分子机制。当我们通过手术诱导Col 2a 1-Cre; Runx 1fl/fland Runx 1fl/flmice的关节不稳定性、软骨降解和骨赘形成来分析Col 2a 1-Cre; Runx 1fl/flmice的OA发展时，与Runx 1fl/flmice的关节相比，手术后8周，Col 2a 1-Cre; Runx 1fl/flmice的关节加速。为了研究Runx 1对软骨细胞的调节，我们分析了与辅因子和下游分子的相互作用。Runx 1与Sox 5、Sox 6和Sox 9合作增强软骨基质的产生，并且免疫共沉淀分析显示Runx 1与每个Sox蛋白之间的蛋白质-蛋白质结合。Runx 1的敲除增加了小鼠关节软骨和原代软骨细胞中肥大标志物Co 10a 1的表达。这种表达伴随着Bapx 1的表达减少，Bapx 1是肥大分化的有效抑制因子。值得注意的是，Runx 1诱导的肥大性分化的抑制被Bapx 1的siRNA沉默所减弱，而软骨形成标记物没有改变。因此，Runx 1有助于关节软骨的维护，通过增强基质生产与Sox蛋白的合作，并抑制肥大分化至少部分通过Bapx 1诱导。
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 ofCOL2A1, 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 inCol2a1-Cre;Runx1fl/flandRunx1fl/flmice by surgically inducing joint instability, Cartilage degradation and osteophyte formation ofCol2a1-Cre;Runx1fl/fljoints was accelerated compared with joints inRunx1fl/flanimals 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 ofBapx1, 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.