FBS Colloquia No.390Laboratory of Tissue Biochemistry

Elucidation of the molecular mechanisms by which aberrant FGFR3 signaling disrupts stem cell properties of growth plate chondrocytes in achondroplasia

Achondroplasia, a prototypical skeletal disorder characterized by limb shortening, results from gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3) within growth plate cartilage. While FGFR3 signaling is known to regulate cellular proliferation and differentiation critical for longitudinal bone growth, the precise mechanisms underlying growth arrest remain incompletely understood. In this study, we generated novel knock-in mice harboring human disease-equivalent FGFR3 mutations, revealing pathological expansion of specific zones within the growth plate and significant bone length reduction. Through comprehensive lineage tracing, we demonstrated that hyperactive FGFR3 signaling compromises both self-renewal capacity and differentiation potential of skeletal stem-like cells, directly contributing to growth impairment. This seminar presents novel insights into previously overlooked zonal pathomechanisms within the growth plate and explores emerging therapeutic strategies targeting these cellular processes.