Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth

Abstract

Endochondral ossification is a major mode of bone that occurs as chondrocytes undergo proliferation, hypertrophy, cell death, and osteoblastic replacement. We have identified a role for fibroblast growth factor receptor 3 (FGFR-3) in this process by disrupting the murine Fgfr-3 gene to produce severe and progressive bone dysplasia with enhanced and prolonged endochondral bone growth. This growth is accompanied by expansion of proliferating and hypertrophic chondrocytes within the cartilaginous growth plate. Thus, FGFR-3 appears to regulate endochondral ossification by an essentially negative mechanism, limiting rather than promoting osteogenesis. In light of these mouse results, certain human disorders, such as achondroplasia, can be interpreted as gain-of-function mutations that activate the fundamentally negative growth control exerted by the FGFR-3 kinase.

Human CYR61-mediated enhancement of bFGF-induced DNA synthesis in human umbilical vein endothelial cells

“…We have shown that Cyr61 can directly promote the chondrogenic di erentiation of mouse limb mesenchymal cells in micromass cultures (Wong et al, 1998). Given the role of FGF signaling mechanism in development of the embryonic skeleton (Niu et al, 1997;Muenke and Schell, 1995;Ishigaki et al, 1997;Deng et al, 1997), it remains possible that CYR61 may interact and cooperate with FGF function in this organ system.…”

A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

“…Homologous recombination in ES cells and generation of germline chimeras TC1 ES cells (Deng et al, 1996) were transfected with NotI digested pBrca1neo and selected with G418 and FIAU. The culture, electroporation, and selection of TC1 cells was carried out as described .…”

Fibroblast growth factor receptor 2 (Fgfr2) plays an important role in eyelid and skin formation and patterning

“…The isolation, culture, and injection of ES cells were performed as described previously (Deng et al, 1996). For ␤-galactosidase staining, embryos were washed in PBS with 2 mM MgCl 2 , 0.01% Nadeoxycholate, 0.02% NP-40 for 30 -60 min, then stained in X-gal overnight at 37°C as described (Mansour et al, 1993).…”

“…Gene targeting in mice shows that Fgfr1-null embryos die before E9.5 displaying severe growth retardation, cell migration defects, and defective mesodermal structures (Ciruna, 1997;Deng et al, 1994Deng et al, , 1996Yamada et al, 1994). Fgfr1␣-isoform knock-outs die at E9.5-12.5 due to the failure of axial mesoderm cell migration toward the posterior portions of the embryos.…”