title: Hypoxia-Induced Fibroblast Growth Factor 11 Stimulates Osteoclast-Mediated Resorption of Bone.
abstract: Over-activation of osteoclasts is directly responsible for pathological bone loss in conditions such as rheumatoid arthritis and cancer metastasis to bone. Hypoxia is a common feature of these conditions, associated with poor prognosis, which also stimulates osteoclast-mediated bone resorption via induction of the hypoxia-inducible transcription factor HIF-1α. Here, we investigate the effects of fibroblast growth factor 11 (FGF11) on osteoclast function. FGF11 is an intracellular FGF that was induced both by hypoxia (2% O2, p < 0.01) and by inhibition of the HIF-regulating prolyl hydroxylase enzymes (CoCl2, p < 0.001) in osteoclasts. Isoform-specific siRNA demonstrated that the induction of Fgf11 mRNA expression by hypoxia is HIF-1α-dependent (p < 0.01). Hypoxic stimulation of bone resorption was inhibited in osteoclasts treated with siRNA targeting FGF11 (p < 0.05). This was at least partially due to reduced secretion of an unidentified pro-resorptive factor downstream of FGF11. FGF11 expression within hypoxic, resorbing osteoclasts co-localised with microtubule-associated alpha-tubulin. FGF11 was also abundantly expressed in osteoclasts within the rheumatoid synovium and in giant cell tumour of bone. This study suggests FGF11 as a novel factor driving pathological bone resorption in osteolytic disease and as a potential target for the development of new anti-resorptive therapeutic agents.
authors.affiliation: Botnar Research Centre, Nuffield Department of Orthopaedics Rheumatology & Musculoskeletal Sciences, University of Oxford, Headington, Oxford, OX3 7LD, UK. helen.knowles@ndorms.ox.ac.uk.
authors.forename: Helen J
authors.identifier: 0000-0002-9575-6067
authors.initials: HJ
authors.lastname: Knowles
mesh_terms: D001862:Bone Resorption / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010010:Osteoclasts / Q000378:metabolism*
chemical_list: C000609548:FGF11 protein, human; D005346:Fibroblast Growth Factors
keywords: Bone resorption; Hypoxia-inducible factor-1 alpha (HIF-1α); Microtubule; Osteoclast; Rheumatoid arthritis