Zhou Siru, Xie Yangli, Tang Junzhou, Huang Junlan, Huang Qizhao, Xu Wei, Wang Zuqiang, Luo Fengtao, Wang Quan, Chen Hangang, Du Xiaolan, Shen Yue, Chen Di, Chen Lin
Center of Bone Metabolism and Repair, Department of Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, United States of America.
PLoS Genet. 2015 Jun 19;11(6):e1005214. doi: 10.1371/journal.pgen.1005214. eCollection 2015 Jun.
Most cartilaginous tumors are formed during skeletal development in locations adjacent to growth plates, suggesting that they arise from disordered endochondral bone growth. Fibroblast growth factor receptor (FGFR)3 signaling plays essential roles in this process; however, the role of FGFR3 in cartilaginous tumorigenesis is not known. In this study, we found that postnatal chondrocyte-specific Fgfr3 deletion induced multiple chondroma-like lesions, including enchondromas and osteochondromas, adjacent to disordered growth plates. The lesions showed decreased extracellular signal-regulated kinase (ERK) activity and increased Indian hedgehog (IHH) expression. The same was observed in Fgfr3-deficient primary chondrocytes, in which treatment with a mitogen-activated protein kinase (MEK) inhibitor increased Ihh expression. Importantly, treatment with an inhibitor of IHH signaling reduced the occurrence of chondroma-like lesions in Fgfr3-deficient mice. This is the first study reporting that the loss of Fgfr3 function leads to the formation of chondroma-like lesions via downregulation of MEK/ERK signaling and upregulation of IHH, suggesting that FGFR3 has a tumor suppressor-like function in chondrogenesis.
大多数软骨肿瘤在骨骼发育过程中于生长板附近形成，这表明它们起源于软骨内骨生长紊乱。成纤维细胞生长因子受体（FGFR）3信号在此过程中发挥着重要作用；然而，FGFR3在软骨肿瘤发生中的作用尚不清楚。在本研究中，我们发现出生后软骨细胞特异性Fgfr3缺失会诱导多个软骨瘤样病变，包括内生软骨瘤和骨软骨瘤，这些病变位于紊乱的生长板附近。这些病变显示细胞外信号调节激酶（ERK）活性降低，印度刺猬因子（IHH）表达增加。在Fgfr3缺陷的原代软骨细胞中也观察到同样情况——用丝裂原活化蛋白激酶（MEK）抑制剂处理可增加Ihh表达。重要的是，用IHH信号抑制剂处理可减少Fgfr3缺陷小鼠中软骨瘤样病变的发生。这是第一项报道Fgfr3功能丧失通过下调MEK/ERK信号和上调IHH导致软骨瘤样病变形成的研究，表明FGFR3在软骨形成中具有肿瘤抑制样功能。
