Abstract
Aberrant fibroblast growth factor receptor 3 (FGFR3) signaling disrupts chondrocyte proliferation and growth plate size and architecture, leading to various chondrodysplasias or bone overgrowth. These observations suggest that the duration, intensity and cellular context of FGFR signaling during growth plate chondrocyte maturation require tight, regulated control for proper bone elongation. However, the machinery fine-tuning FGFR signaling in chondrocytes is incompletely defined. We report here that neurofibromin, a Ras-GAP encoded by Nf1, has an overlapping expression pattern with FGFR1 and FGFR3 in prehypertrophic chondrocytes, and with FGFR1 in hypertrophic chondrocytes during endochondral ossification. Based on previous evidence that neurofibromin inhibits Ras-ERK signaling in chondrocytes and phenotypic analogies between mice with constitutive FGFR1 activation and Nf1 deficiency in Col2a1-positive chondrocytes, we asked whether neurofibromin is required to control FGFR1-Ras-ERK signaling in maturing chondrocytes in vivo. Genetic Nf1 ablation in Fgfr1-deficient chondrocytes reactivated Ras-ERK1/2 signaling in hypertrophic chondrocytes and reversed the expansion of the hypertrophic zone observed in mice lacking Fgfr1 in Col2a1-positive chondrocytes. Histomorphometric and gene expression analyses suggested that neurofibromin, by inhibiting Rankl expression, attenuates pro-osteoclastogenic FGFR1 signaling in hypertrophic chondrocytes. We also provide evidence suggesting that neurofibromin in prehypertrophic chondrocytes, downstream of FGFRs and via an indirect mechanism, is required for normal extension and organization of proliferative columns. Collectively, this study indicates that FGFR signaling provides an important input into the Ras-Raf-MEK-ERK1/2 signaling axis in chondrocytes, and that this input is differentially regulated during chondrocyte maturation by a complex intracellular machinery, of which neurofibromin is a critical component.
Highlights
Endochondral bone formation is a complex, highly regulated and orderly multi-step process by which long bones elongate during development and heal following fracture
Fgfr1 expression overlapped with Nf1 expression in the prehypertrophic, hypertrophic and perichondrium areas, while Fgfr3 expression only overlapped with Nf1 expression in prehypertrophic chondrocytes at both P0 and P7
Coexpression does not prove functional interaction, these results suggest that neurofibromin may regulate FGFR1 signaling rather than fibroblast growth factor receptor 3 (FGFR3) signaling in hypertrophic growth plate chondrocytes
Summary
Endochondral bone formation is a complex, highly regulated and orderly multi-step process by which long bones elongate during development and heal following fracture. It relies on tight spatiotemporal interactions and crosstalk between growth factors and signaling from their receptors in target cells, including osteochondroprogenitors, chondrocytes, osteoblasts and osteoclasts. Proper signaling within the growth plate between chondrocytes and with neighboring cells is essential for the successful and timely transition of resting chondrocytes to proliferating and hypertrophic chondrocytes [1,2]. Fibroblast growth factor (FGF) signaling during endochondral bone formation has been the subject of intense scientific inquiry. The receptors for FGFs (mainly FGFR3 and FGFR1) were shown to be expressed in distinct zones: FGFR3 in
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