Skeletal disorders associated with fibroblast growth factor receptor mutatios

doi:10.1016/S0959-437X(97)80152-9

Current Opinion in Genetics & Development

Volume 7, Issue 3, June 1997, Pages 378-385

https://doi.org/10.1016/S0959-437X(97)80152-9 Get rights and content

Abstract

Mutations in three fibroblast growth factor receptor loci underlie several autosomal dominant skeletal disorders; these include dwarfism and various craniosynostosis syndromes affecting limb and craniofacial bone patterning. A functional analysis of several of these mutations has demonstrated that a constitutive activation of the receptor kinase is a common theme.

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BFGF (also called FGF-2) found in bone matrix48,49 is a multifunctional factor that induces proliferation and morphogenesis in a wide range of cells and tissues, including the PDL.14 BFGF also appears to exert profound effects on bone growth and development,50,51 and enhances fracture healing.52 Moreover, bFGF inhibits alkaline phosphatase activity and PDL cell mineralized nodule formation in vitro.10
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Systemically administered fibroblast growth factors (FGFs) show anabolic effects on bone formation in animals, whereas in vitro cell culture studies have demonstrated that FGFs block mineralized bone nodule formation. These apparently contradictory outcomes indicate that the nature of FGF action is complex and that the biological effect of FGFs may depend on the differentiation stage of osteoblasts, interaction with other cytokines, or the length and mode of exposure to factors. Thus, we have utilized primary calvarial bone cell populations at different maturation phases to determine their responses to 2, FGF-9, and BMP-2, the factors expressed in bone. FGF-2 and FGF-9 stimulated proliferation of the cell populations consisting of more mature osteoblasts, but not those with undifferentiated precursor cells. Continuous treatment with FGF-2/-9 inhibited expression of several osteoblast marker genes and mineralization. However, brief pretreatment with FGF-2/-9 or sequential treatment with FGF-2/-9 followed by BMP-2 led to marked stimulation of mineralization, suggesting that FGFs enhance the intrinsic osteogenic potential. Furthermore, FGF-2 and FGF-9 increased expression of other osteogenic factors BMP-2 and TGFβ-1. Meanwhile, blocking endogenous FGF signaling, using a virally transduced dominant-negative FGF receptor (FgfR), resulted in drastically reduced expression of the BMP-2 gene, demonstrating for the first time that endogenous FGF/FgfR signaling is a positive upstream regulator of the BMP-2 gene in calvarial osteoblasts. In contrast, expression of a BMP antagonist noggin was inhibited by FGF-2 and FGF-9. Thus, collective data from this study suggest that FGF/FgfR signaling enhances the intrinsic osteogenic potential by selectively expanding committed osteogenic cell populations as well as inversely regulating BMP-2 and noggin gene expression.
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Colonic atresia occurs in 1:20,000 live births, offering a neonatal surgical challenge. Prenatal expression of fibroblast growth factor 10 (Fgf10), acting through fibroblast growth factor receptor 2b (Fgfr2b), is critical to the normal development of the colon. Invalidation of the Fgf10 pathway results in colonic atresia, inherited in an autosomal recessive pattern. Classically, disturbance of the mesenteric vasculature has been thought to cause many forms of intestinal atresia. The purpose of this study was to evaluate the role of vascular occlusion in the pathogenesis of colonic atresia.
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Skeletal disorders associated with fibroblast growth factor receptor mutatios

Abstract

Trends Genet

Curr Opin Genet Dev

Cell

Adv Cancer Res

J Biol Chem

Cell

J Biol Chem

J Biol Chem

Cell

Cell

Nat Genet

Nat Genet

J Biol Chem

Development

J Biol Chem

Nat Genet

Nat Genet

Am J Hum Genet

Functions of fibroblast growth-factors and their receptors

Curr Biol

Mutations in fibroblast growth factor receptors: phenotypic consequences during eukaryotic development

Am J Hum Genet

Structural and functional diversity in the FGF receptor multigene family

Adv Cancer Res

Promiscuity of fibroblast growth-factor receptors

Bioessays

FGF binding and FGF receptor activation by synthetic heparan-derived disaccharides and trisaccharides

Science

The heparin binding (fibroblast) growth factor family proteins

Annu Rev Biochem

Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia

Nature

Thanatophoric dysplasia (type-I and type-II) caused by distinct mutations in fibroblast growth-factor receptor-3

Nat Genet

Stop codon FGFR3 mutations in thanatophoric dwarfism type 1

Nat Genet

Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type-1 (td1)

Hum Mol Genet

Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type-1

Hum Mol Genet

A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia

Nat Genet

Clinical and genetic heterogeneity of hypochodroplasia

J Med Genet

A common FGFR3 gene mutation in hypochondroplasia

Hum Mol Genet

Constitutive activation of fibroblast growth-factor receptor-3 by the transmembrane domain point mutation found in achondroplasia

EMBO J

Graded activation of fibroblast growth-factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia

Nat Genet