骨关节炎是引起中老年人残疾的最常见的骨科疾病之一。软骨细胞异常成熟和钙化被认为是骨关节炎常见的病理变化和最主要的致病机制。经典Wnt信号通路在软骨内成骨过程中，对软骨细胞的肥大和钙化起促进作用，而小G蛋白RAC1在Wnt信号通路中，促进β-catenin向细胞核内转运，但是否促进软骨细胞的肥大和钙化目前尚不清楚。我们的前期研究证明：骨关节炎病变组织中RAC1-GTP活性成分的含量明显升高，体外用NSC23766沉默了Rac1基因可以明显抑制软骨细胞的钙化。因此，通过沉默Rac1在Wnt信号通路中的作用，抑制软骨细胞的钙化极可能是治疗骨关节炎的有效手段。本课题组将通过体外分离培养软骨细胞，体内应用条件性敲除基因小鼠和Rac1抑制剂，以软骨修复作为模型研究RAC1在骨关节炎发病所起到的作用及其内在的机理，为骨关节炎的治疗提供新思路、新手段。

Osteoarthritis (OA) is the leading cause of disability in older people. Recently, pathological hypertrophy and maturation of chondrocytes have been recgonized as a most possible dominant cause of OA, and canonical Wnt signaling pathway has been demonstrated to have an important role in stimulating chondrocytes maturation. RAC1 functions to translocate b-catenin into nucleus and acts as a pivotal role in canonical Wnt signaling. However, the role of RAC1 in the process of pathological hypertrophy and maturation of chondrocytes is still not clear. Our pilot study found that RAC1 was activated in Osteoarthritis chondrocytes and down-regulation of Rac1 by NSC23766 (Rac1 inhibitor) in vitro significantly inhibits chondrocytes ossification. So, it is likely that regulation of Rac1 in canonical Wnt signaling controls chondrocytes maturation and ossification in the pathogenesis of osteoarthritis. We will isolate and culture chondrocytes from cartilage tissue in vitro, utilize cartilage regeneration as model and Rac1 inhibitor NSC23766 and conditional gene knock out mouse as tools to explore the role of RAC1 in the pathogenesis of OA and may supply a new target for osteoarthritis therapy.

骨关节炎是常见的慢性退行性关节病，尽管其病因并不明确，但是软骨细胞的异常肥大与钙化被认为在骨关节炎病理发展中起到重要作用。Wnt/β-catenin信号通路在软骨细胞分化以及肥大中发挥主要功能。而小G蛋白RAC1参与Wnt信号通路中β-catenin信号的转导。研究结果显示RAC1的活性成分在骨关节炎患者关节软骨中的含量有着明显的提高。小鼠骨关节炎造模后显示，关节软骨中Rac1的活性也有明显的增强。即骨关节炎中Rac1可以被明显激活。体外软骨细胞加入IL-1刺激，模拟体内骨关节炎炎症环境后，Rac1的活性成分显著增加。体外软骨细胞中过表达RAC1后，可见软骨细胞钙化明显增强；而沉默Rac1后可见软骨细胞肥大与钙化明显减弱。我们随后用了RAC1活性抑制剂，进行软骨细胞诱导培养后，同样可以发现软骨细胞形成钙结节的能力明显减弱。为进一步探究Rac1促进软骨细胞肥大钙化的机制，在过表达RAC1的软骨细胞中，运用突变体沉默β-catenin，用来抑制β-catenin的信号传导，结果显示软骨细胞的钙化能力明显减弱，而β-catenin主要通过促进RUNX2的转录活性促进软骨细胞肥大钙化。关节炎模型小鼠关节腔注射RAC1的抑制剂后，我们发现关节软骨基质的降解得到了保护，而且关节软骨细胞肥大相关基因的表达也得到了抑制。综上，研究结果证明了骨关节炎中RAC1活性的提高能够促进软骨细胞肥大，进而促进了骨关节炎的进展。抑制RAC1的活性（譬如使用RAC1抑制剂）可能是控制骨关节炎疾病进展的新方向。