FIBROBLAST GROWTH-FACTOR RECEPTOR-3 MUTATIONS PROMOTE APOPTOSIS BUT DO NOT ALTER CHONDROCYTE PROLIFERATION IN THANATOPHORIC DYSPLASIA

Thanatophoric dysplasia (TD) is a lethal skeletal disorder caused by r ecurrent mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene. The mitogenic response of fetal TD I chondrocytes in primary cu ltures upon stimulation by either FGF 2 or FGF 9 did not significantly differ from controls. Although the levels of FGFR 3 mRNAs in cultured TD chondrocytes were similar to controls, an abundant immunoreactive material was observed at the perinuclear level using an anti-FGFR 3 an tibody in TD cells. Transduction signaling via the mitogen-activated p rotein kinase pathway was assessed by measuring extracellular signal-r egulated kinase activity (ERK 1 and ERK 2). Early ERKs activation foll owing FGF 9 supplementation was observed in TD chondrocytes (2 min) as compared with controls (5 min) but no signal was detected in the abse nce of ligand, By contrast ligand-independent activation of the STAT s ignaling pathway was demonstrated in cultured TD cells and confirmed b y immunodetection of Stat 1 in the nuclei of hypertrophic TD chondrocy tes. Moreover, the presence of an increased number of apoptotic chondr ocytes in TD fetuses was associated with a higher expression of Bar an d the simultaneous decrease of Bcl-2 levels. Taken together, these res ults indicate that FGFR 3 mutations in TD I fetuses do not hamper chon drocyte proliferation but rather alter their differentiation by trigge ring premature apoptosis through activation of the STAT signaling path way.