Constitutive activation of activin receptor-like kinase 3 in chondrocytes exacerbates skeletal dysplasia in mice with achondroplasia.

Abstract

Achondroplasia (ACH), the most common skeletal dysplasia in humans, is caused by gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3). Activation of FGFR3 and its downstream signaling pathways lead to disturbed chondrogenesis in ACH. Nevertheless, the pathogenic mechanism of ACH has yet not been fully elucidated. Previous studies have indicated that FGF and BMP signaling may have opposing actions on the growth plate development. To clarify the crosstalk between FGFR3 and activin receptor-like kinase 3 (ALK3) signaling in ACH, we generated caALK3col2-ACH mice expressing a constitutively active mutant of ALK3 in the chondrocytes of mice with ACH resulting from a Gly369Cys mutation in FGFR3. Unexpectedly, these mice exhibited a more severe chondrodysplasia phenotype than ACH mice, as evidenced by a greater decrease in chondrocyte proliferation and impaired hypertrophy of chondrocytes in the growth plates. These changes were correlated with an increased expression of p21 and activation of ERK/MAPK pathway. This study provides an in vivo genetic demonstration of the imbalanced interaction between the FGFR3 and ALK3 signaling pathways in the growth plate of caALK3col2-ACH mice, suggesting that the ERK/MAPK pathway play an essential role in growth plate chondrogenesis.