Conditional Deletion of Fgfr3 in Chondrocytes leads to Osteoarthritis-like Defects in Temporomandibular Joint of Adult Mice.
Conditional Deletion of Fgfr3 in Chondrocytes leads to Osteoarthritis-like Defects in Temporomandibular Joint of Adult Mice.
复制标题
软骨细胞中 Fgfr3 的条件性缺失导致成年小鼠颞下颌关节骨关节炎样缺陷
DOI：
10.1038/srep24039
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发表时间：
2016-04-04
影响因子：
4.6
通讯作者：
Chen L
中科院分区：
文献类型：
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作者：
Zhou S;Xie Y;Li W;Huang J;Wang Z;Tang J;Xu W;Sun X;Tan Q;Huang S;Luo F;Xu M;Wang J;Wu T;Chen L;Chen H;Su N;Du X;Shen Y;Chen L
颞下颌关节（TMJ）骨关节炎（OA）是成人常见的退行性疾病，其特征是关节软骨进行性破坏。为了研究FGFR 3在成年阶段TMJ软骨稳态中的作用，我们产生了Fgfr 3f/f; Col 2a 1-CreERT 2（Fgfr 3 cKO）小鼠，其中Fgfr 3在2月龄时在软骨细胞中缺失。在Fgfr 3 cKO TMJ软骨中观察到OA样缺损。免疫组织化学染色和实时定量PCR分析显示，COL 10，MMP 13和AMAMTS 5的表达显着增加。此外，Fgfr 3 cKO关节面软骨细胞凋亡急剧增加，并伴有润滑素表达下调。重要的是，RUNX 2和Indian hedgehog（IHH）的表达在Fgfr 3 cKO TMJ中上调。用IHH信号传导抑制剂处理原代Fgfr 3 cKO软骨细胞，其显著降低Runx 2、Col 10、Mmp 13和Adamts 5的表达。此外，IHH信号传导抑制剂部分缓解了Fgfr 3 cKO小鼠TMJ中的OA样缺陷，包括恢复润滑素表达和改善关节面的完整性。本研究提示FGFR 3/IHH信号通路在维持成年期TMJ关节软骨的稳态中起着重要作用。
Osteoarthritis (OA) in the temporomandibular joint (TMJ) is a common degenerative disease in adult, which is characterized by progressive destruction of the articular cartilage. To investigate the role of FGFR3 in the homeostasis of TMJ cartilage during adult stage, we generated Fgfr3f/f; Col2a1-CreERT2 (Fgfr3 cKO) mice, in which Fgfr3 was deleted in chondrocytes at 2 months of age. OA-like defects were observed in Fgfr3 cKO TMJ cartilage. Immunohistochemical staining and quantitative real-time PCR analyses revealed a significant increase in expressions of COL10, MMP13 and AMAMTS5. In addition, there was a sharp increase in chondrocyte apoptosis at the Fgfr3 cKO articular surface, which was accompanied by a down-regulation of lubricin expression. Importantly, the expressions of RUNX2 and Indian hedgehog (IHH) were up-regulated in Fgfr3 cKO TMJ. Primary Fgfr3 cKO chondrocytes were treated with IHH signaling inhibitor, which significantly reduced expressions of Runx2, Col10, Mmp13 and Adamts5. Furthermore, the IHH signaling inhibitor partially alleviated OA-like defects in the TMJ of Fgfr3 cKO mice, including restoration of lubricin expression and improvement of the integrity of the articular surface. In conclusion, our study proposes that FGFR3/IHH signaling pathway plays a critical role in maintaining the homeostasis of TMJ articular cartilage during adult stage.