FGF signaling in the developing endochondral skeleton

Abstract

Mutations in fibroblast growth factor receptors (Fgfrs) are the etiology of many craniosynostosis and chondrodysplasia syndromes in humans. The phenotypes associated with these human syndromes and the phenotypes resulting from targeted mutagenesis in the mouse have defined essential roles for FGF signaling in both endochondral and intramembranous bone development. In this review, I will focus on the role of FGF signaling in chondrocytes and osteoblasts and how FGFs regulate the growth and development of endochondral bone. KeywordsFGF; Skeletal development; Craniosynostosis; Achondroplasia; Receptor tyrosine kinase Human skeletal disease syndromes: the FGF connectionFgfrs were known to be expressed in the developing skeleton. However, a functional link between FGF signaling and skeletal development was not appreciated until the discovery that achondroplasia (ACH), the most common form of skeletal dwarfism in humans, was caused by a missense mutation in Fgfr3 [1][2][3][4][5]. Following this initial discovery, a milder form of dwarfism, hypochondroplasia (HCH) [6,7], and a more severe form of dwarfism, thanatophoric dysplasia (TD) [3,[8][9][10], were also found to result from mutations in Fgfr3.In addition to the chondrodysplasia syndromes, many other human skeletal dysplasias have been attributed to mutations in Fgfrs 1, 2 and 3 [11][12][13][14][15][16][17]. These disorders have in common craniosynostosis (premature fusion of the cranial sutures) and variably other phenotypes that affect the appendicular skeleton and other organ systems. The craniosynostosis syndromes involving Fgfr2 include Apert syndrome (AS) [18], Beare-Stevenson cutis gyrata [19], Crouzon syndrome (CS) [20][21][22][23][24][25][26][27][28][29][30][31][32], Pfeiffer syndrome (PS) [33][34][35][36][37]23,28,29], Jackson-Weiss syndrome (JWS) [22,23,26] and a non-syndromic craniosynostosis (NSC) [38]. Recently a family has been described with a double mutation in Fgfr2 (S2521, A315S) that is associated with syndactyly but not craniosynostosis [39]. However, individually, these mutations are associated with low-penetrance craniosynostosis.In addition to the single mutation in Fgfr1 (P252R) that causes Pfeiffer syndrome [40][41][42]29], a rare mutation has been identified that causes osteoglophonic dysplasia (OD), a disease characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as the rhizomelic dwarfism and nonossifying bone lesions [43]. One patient has also been described with Jackson-Weiss syndrome and a P252R mutation in Fgfr1 Recently, a mutation in Fgfr3 (P250R) has been described that causes Muenke syndrome (MS), which is characterized by craniosynostosis and variably other skeletal and neurological phenotypes [38,46,47]. Another mutation in Fgfr3 (A391E) causes Crouzon syndrome with acanthosis nigricans, now referred to as crouzonodermoskeletal syndrome [48][49][50][51][52]24].All of the skeletal disease syndromes are caused by autosomal dominant mutations and frequently arise sporadically...

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