Rationale: Cartilage stem/progenitor cells (CSPC) are a promising cellular source to promote endogenous cartilage regeneration in osteoarthritis (OA). Our previous work indicates that ribosomal s6 kinase 3 (RSK-3) is a target of 4-aminobiphenyl, a chemical enhancing CSPC-mediated cartilage repair in OA. However, the primary function and mechanism of RSK-3 in CSPC-mediated cartilage pathobiology remain undefined./nMethods: We systematically assessed the association of RSK-3 with OA in three mouse strains with varying susceptibility to OA (MRL/MpJ>CBA>STR/Ort), and also RSK-3^-/- mice. Bioinformatic analysis was used to identify the possible mechanism of RSK-3 affecting CSPC, which was further verified in OA mice and CSPC with varying RSK-3 expression induced by chemicals or gene modification./nResults: We demonstrated that the level of RSK-3 in cartilage was positively correlated with cartilage repair capacities in three mouse strains (MRL/MpJ>CBA>STR/Ort). Enhanced RSK-3 expression by 4-aminobiphenyl markedly attenuated cartilage injury in OA mice and inhibition or deficiency of RSK-3 expression, on the other hand, significantly aggravated cartilage damage. Transcriptional profiling of CSPC from mice suggested the potential role of RSK-3 in modulating cell proliferation. It was further shown that the in vivo and in vitro manipulation of the RSK-3 expression indeed affected the CSPC proliferation. Mechanistically, ribosomal protein S6 (rpS6) was activated by RSK-3 to accelerate CSPC growth./nConclusion: RSK-3 is identified as a key regulator to enhance cartilage repair, at least partly by regulating the functionality of the cartilage-resident stem/progenitor cells.

中文翻译：

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RSK-3通过与软骨干/祖细胞中的rpS6相互作用来促进软骨再生。

原理：软骨干/祖细胞（CSPC）是一种有希望的细胞来源，可促进骨关节炎（OA）中内源性软骨再生。我们以前的工作表明核糖体s6激酶3（RSK-3）是4-氨基联苯的靶标，4-氨基联苯是一种化学增强CSPC介导的OA软骨修复的药物。然而，RSK-3在CSPC介导的软骨病理生物学中的主要功能和机制尚不清楚。/n方法：我们系统地评估了三种对OA易感性的小鼠品系中RSK-3与OA的关联（MRL / MpJ> CBA > STR / Ort），以及RSK-3 ^-/-老鼠。生物信息学分析用于确定RSK-3影响CSPC的可能机制，该作用已在OA小鼠和CSPC中进一步验证，其化学或基因修饰诱导RSK-3表达变化。我们证明了三种小鼠品系（MRL / MpJ> CBA> STR / Ort）中软骨中RSK-3的水平与软骨修复能力呈正相关。另一方面，由4-氨基联苯增强的RSK-3表达可显着减轻OA小鼠的软骨损伤，并抑制或缺乏RSK-3表达，从而显着加重了软骨损伤。小鼠CSPC的转录谱分析表明RSK-3在调节细胞增殖中的潜在作用。进一步显示RSK-3表达的体内和体外操作确实影响CSPC增殖。从机理上讲，核糖体蛋白S6（rpS6）被RSK-3激活以加速CSPC的生长。 RSK-3被认为是增强软骨修复的关键调节剂，至少部分通过调节软骨驻留干/祖细胞的功能来实现。