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  • Regulation of FGF signalling is critical to ensure


    Regulation of FGF signalling is critical to ensure a balanced response to receptor stimulation. This occurs largely through negative feedback mechanisms, including receptor internalisation via ubiquitination (Wang et al., 2002) and induction of negative regulators, for example SPRY, SPRED 1 and 2 and SEF (Hacohen et al., 1998, Kovalenko et al., 2003, Torii et al., 2004, Wakioka et al., 2001, Yang et al., 2003) (Fig. 1). A further level of control exists in the form of receptor autoinhibition (Plotnikov et al., 1999, Schlessinger et al., 2000, Stauber et al., 2000). Electrostatic bonding between the ciprofloxacin box and the HS-binding site induces a closed, autoinhibited conformation (Kalinina et al., 2012, Olsen et al., 2004) (Fig. 2). This mechanism of autoinhibition supports FGF binding specificity of receptors; only specific ligands with high affinity for the receptors will overcome the inhibition and bind to the receptor.
    FGFR signalling in cancer
    FGFRs as therapeutic targets
    Concluding remarks
    Introduction Statins are established inhibitors of a rate-limiting enzyme in cholesterol synthesis, the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), and as such are widely prescribed for cholesterol lowering. Long-term studies show that statins influence other physiological processes as well, including endothelial cell function, inflammatory response, cell proliferation and bone metabolism, suggesting pleiotropic effects beyond HMGR inhibition. Recently, statins have been reported to experimentally rescue the aberrant fibroblast growth factor receptor (FGFR3) signaling in the models of achondroplasia (ACH) and thanatophoric dysplasia (TD), the two genetic human dwarfing conditions caused by gain-of-function mutations in FGFR3. ACH and TD are manifested by a malformed and hypoplastic skeleton, due to profound inhibition of chondrocyte proliferation and differentiation within the growth plate cartilage4, 5, 6. The anabolic statin effect on bone formation and their preventive effect on articular chondrocyte aging and degeneration were previously described, in the context of osteoporosis or arthritis7, 8, but never in relation to FGFR signaling in the growth plate cartilage. In a recent study, Yamashita et al. demonstrated a statin-mediated recovery of impaired chondrogenic differentiation mediated by constitutively active FGFR3 in induced pluripotent stem (iPS) cells established from the skin of ACH and TD patients. In addition, statins caused bone elongation and rescued the overall growth inhibitory phenotype in a genetic mouse model of human ACH. Interestingly, no significant statin effect on skeletal growth was found in wildtype (WT) animals. This is in contrast to the elevated growth in WT mice or cynomolgus monkeys where FGFR3 signaling was inhibited via a stable analog of C-natriuretic peptide, which is in agreement with the fact that FGFR3 is a physiological negative regulator of skeletal growth. It has been suggested that statins may mediate downregulation of mutated but not WT FGFR3 protein. The accumulation of FGFR3 observed in TD iPS-derived cartilage is in agreement with earlier studies reporting similar accumulation of FGFR3 in human ACH growth plates or mouse models of both ACH and TD11, 12, 13. This accumulation depends on the level of FGFR3 activity and may be due to the defective ubiquitination and proteasome targeting in FGFR3 mutants lacking lysine residues (such as p.K650E substitution associated with TD) and/or inhibitory FGFR3-mediated phosphorylation of c-Cbl ubiquitin ligase known to be involved in FGFR3 downregulation14, 15, 16. It is presently unclear how statins influence any of the abovementioned processes. Altogether, the elucidation of the molecular mechanism of statin-mediated regulation of FGFR3 signaling may uncover novel roles of cholesterol or other possible statin targets in chondrocyte biology, and facilitate statin application for treatment of FGFR3-related chondrodysplasias. This study was undertaken to unravel the mechanism of statin effect on FGFR3 stability and signaling in several experimental models of FGFR3 signaling in chondrocyte cell environment, such as cultured chondrocyte cell lines, ex vivo embryonal tibia cultures, and in the limb bud micromass cultures induced to differentiate into chondrocytes.