FGFR3 induces degradation of BMP type I receptor to regulate skeletal development.

[achondroplasia]

Fibroblast growth factors (FGFs ) and their receptors (FGFRs ) play significant roles in vertebrate organogenesis and morphogenesis . FGFR 3 is a negative regulator of chondrogenesis and multiple mutations with constitutive activity of FGFR 3 result in achondroplasia , one of the most common dwarfisms in humans , but the molecular mechanism remains elusive . In this study , we found that chondrocyte-specific deletion of BMP type I receptor a (Bmpr 1 a ) rescued the bone overgrowth phenotype observed in Fgfr 3 deficient mice by reducing chondrocyte differentiation . Consistently , using in vitro chondrogenic differentiation assay system , we demonstrated that FGFR 3 inhibited BMPR 1 a-mediated chondrogenic differentiation . Furthermore , we showed that FGFR 3 hyper-activation resulted in impaired BMP signaling in chondrocytes of mouse growth plates . We also found that FGFR 3 inhibited BMP-2 - or constitutively activated BMPR 1 -induced phosphorylation of Smads through a mechanism independent of its tyrosine kinase activity . We found that FGFR 3 facilitates BMPR 1 a to degradation through Smurf 1 -mediated ubiquitination pathway . We demonstrated that down-regulation of BMP signaling by BMPR 1 inhibitor dorsomorphin led to the retardation of chondrogenic differentiation , which mimics the effect of FGF-2 on chondrocytes and BMP-2 treatment partially rescued the retarded growth of cultured bone rudiments from thanatophoric dysplasia type II mice . Our findings reveal that FGFR 3 promotes the degradation of BMPR 1 a , which plays an important role in the pathogenesis of FGFR 3 -related skeletal dysplasia .

Diseases
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Diseases presenting "induced phosphorylation of smads through a mechanism" symptom

achondroplasia

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