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 (DCKO) mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, DCKO mice showed severe postnatal growth defects that include an ∼50% reduction in body weight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone in DCKO mice, suggesting cell autonomous functions of FGF signaling during postnatal bone formation. Surprisingly, DCKO mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence that revealed a non-cell autonomous feedback pathway regulating Fgf9, Fgf18, and Pthlh expression, which together 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.
FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth
Current address: Orthopedic Institute, Soochow University, China
Currently Viewing Accepted Manuscript - Newer Version Available
Kannan Karuppaiah, Kai Yu, Joohyun Lim, Jianquan Chen, Craig Smith, Fanxin Long, David M. Ornitz; FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development 2016; dev.131722. doi: https://doi.org/10.1242/dev.131722
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