FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth
FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth
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DOI：
10.1242/dev.131722
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发表时间：
2016-05-15
期刊：
影响因子：
4.6
通讯作者：
Ornitz, David M.
中科院分区：
文献类型：
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作者：
Karuppaiah, Kannan;Yu, Kai;Ornitz, David M.
成纤维细胞生长因子 (FGF) 信号传导对于骨骼发育很重要；然而，人们对调节骨生长的细胞特异性功能、冗余和反馈机制知之甚少。 FGF 受体 1 和 2（Fgfr1 和 Fgfr2）均在骨祖细胞谱系中表达。使用骨祖细胞特异性 Cre 驱动程序使两种受体失活的双重条件敲除小鼠在出生时表现正常；然而，这些小鼠表现出严重的出生后生长缺陷，包括体重和骨量减少约 50%，以及纵向骨生长受损。组织学分析显示皮质骨和小梁骨减少，表明 FGF 信号在出生后骨形成过程中具有细胞自主功能。令人惊讶的是，双重条件敲除小鼠还表现出生长板缺陷和软骨细胞增殖停滞。我们提供了调节 Fgf9、Fgf18 和 Pthlh 表达的非细胞自主反馈途径的遗传证据，该途径导致生长板软骨细胞中 Fgfr3 的表达和信号传导增加并抑制软骨细胞增殖。这些观察结果表明，骨祖细胞谱系中的 FGF 信号传导必然与软骨细胞增殖和纵向骨生长的调节相关。
Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage. Double conditional knockout mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, these mice showed severe postnatal growth defects that include an similar to 50% reduction in body-weight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone, suggesting cell-autonomous functions of FGF signaling during postnatal bone formation. Surprisingly, the double conditional knockout mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence of a non-cell-autonomous feedback pathway regulating Fgf9, Fgf18 and Pthlh expression, which led to increased expression and signaling of Fgfr3 in growth plate chondrocytes and suppression of chondrocyte proliferation. These observations show that FGF signaling in the osteoprogenitor lineage is obligately coupled to chondrocyte proliferation and the regulation of longitudinal bone growth.