Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis
Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis
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软骨细胞 FGFR3 通过抑制成骨来调节骨量
DOI：
10.1074/jbc.m116.730093
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发表时间：
2016-11-25
影响因子：
4.8
通讯作者：
Chen, Lin
中科院分区：
文献类型：
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作者：
Wen, Xuan;Li, Xiaogang;Chen, Lin
软骨发生可以调节骨形成。成纤维细胞生长因子受体3在软骨细胞中高度表达，是骨生长的负调节因子。为了研究软骨细胞FGFR 3是否调节骨生成，从而有助于出生后骨形成和骨重建，产生了软骨细胞中Fgfr 3条件性敲除的小鼠（突变体（MUT））。MUT小鼠显示骨过度生长，生长板延长。MUT小鼠的骨量在1月龄和4月龄时均显著增加。组织学分析显示，软骨细胞中Fgfr 3缺失后，成骨细胞数量和骨形成显著增加。软骨细胞-成骨细胞共培养实验进一步显示，软骨细胞中Fgfr 3缺陷通过上调Ihh、Bmp 2、Bmp 4、Bmp 7、Wnt 4和Tgf-β 1的表达，以及下调Nog的表达，促进成骨细胞的分化和矿化。此外，在MUT小鼠中破骨细胞生成也受损，其中内衬骨小梁的破骨细胞数量减少，这可能与Fgfr 3缺陷型软骨细胞中Rankl与Opg的比率降低有关。本研究表明，软骨细胞FGFR 3通过旁分泌机制参与骨形成和骨重建的调节。
Chondrogenesis can regulate bone formation. Fibroblast growth factor receptor 3, highly expressed in chondrocytes, is a negative regulator of bone growth. To investigate whether chondrocyte FGFR3 regulates osteogenesis, thereby contributing to postnatal bone formation and bone remodeling, mice with conditional knock-out of Fgfr3 in chondrocytes (mutant (MUT)) were generated. MUT mice displayed overgrowth of bone with lengthened growth plates. Bone mass of MUT mice was significantly increased at both 1 month and 4 months of age. Histological analysis showed that osteoblast number and bone formation were remarkably enhanced after deletion of Fgfr3 in chondrocytes. Chondrocyte-osteoblast co-culture assay further revealed that Fgfr3 deficiency in chondrocytes promoted differentiation and mineralization of osteoblasts by up-regulating the expressions of Ihh, Bmp2, Bmp4, Bmp7, Wnt4, and Tgf-beta 1, as well as down-regulating Nog expression. In addition, osteoclastogenesis was also impaired in MUT mice with decreased number of osteoclasts lining trabecular bone, which may be related to the reduced ratio of Rankl to Opg in Fgfr3-deficient chondrocytes. This study reveals that chondrocyte FGFR3 is involved in the regulation of bone formation and bone remodeling by a paracrine mechanism.