FGFR3 biology and skeletal disease

Abstract

Fibroblast Growth Factor Receptor 3 (FGFR3) is one of four high-affinity receptors for canonical FGF ligands. It acts in many tissues and plays a special role in skeletal development, especially post-embryonic bone growth, where it inhibits chondrocyte proliferation and differentiation. Gain of function mutations cause the most common forms of dwarfism in humans, and they are also detected in cancer. Triggered by ligand binding or in some cases mutation, FGFR3 activation involves dimerization of receptor monomers, phosphorylation of specific tyrosine residues in the receptor's kinase domain and in the tightly linked scaffold protein Fibroblast Receptor Factor Substrate 2 (FRS2). Signaling molecules recruited to these phosphorylation sites propagate signals through cascades that are subject to modulation. Signal output is also regulated by the fate of the receptor and the interval between its activation and degradation. Trafficking pathways have been identified for both lysosomal and proteasomal degradation, as well as, an alternative fate that involves intramembrane cleavage that produces an intracellular domain fragment capable of nuclear transport and potential function.

Meckel’s and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible

“…In MC, the expression of Fgfr3 was also increased by the Y367C Fgfr3 mutation. It could be the result of a prolonged half time of the protein because the mutation of the transmembrane domain could delay the turnover and degradation of the activated receptor (54,55). …”

The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes

“…The FGF receptor 3 (FGFR3) is a tyrosine kinase receptor, expressed in proliferating chondrocytes and early hypertrophic chondrocytes in the growth plate. Both FGF9 and FGF18 are the major ligands of FGFR3 in the growth plate [ 101 ]. Recently, Shung and coworkers found that FGFR3 expression increases the expression of SOX9 and decreases β-catenin levels in cultured mesenchymal cells [ 102 ].…”

Fibroblast Growth Factor Receptor 3 Inhibits Osteoarthritis Progression in the Knee Joints of Adult Mice

“…For example, FGFR3 is initially expressed by chondrocytes located in the central core of mesenchymal condensation during early development, then in proliferating and pre-hypertrophic zones of growth plates and articular chondrocytes (6). Mutations in FGFR3 have been linked to a variety of human genetic skeletal dysplasias: gain-of-function mutations in FGFR3 result in chondrodysplasias, including achondroplasia (ACH), hypochondroplasia, and thanatophoric dysplasia (TD), while loss-of-function mutations of FGFR3 lead to camptodactyly, tall stature, scoliosis, and hearing loss syndrome in humans (7,8).…”