Hypoxia-induced fibroblast growth factor 11 stimulates osteoclast-mediated resorption of bone

Journal article

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 HIFregulating prolyl hydroxylase enzymes (CoCl2, p< 0.001) in osteoclasts. Isoform-specific siRNA demonstrated that the induction of Fgf11mRNA 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: Knowles, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer
• Journal: Calcified Tissue International
• Volume: 100
• Issue: 4
• Pages: 382–391
• Publication date: 2017-01-01
• Acceptance date: 2016-12-16
• DOI: 10.1007/s00223-016-0228-1
• ISSN: 1432-0827
• Keywords: Osteoclast; Bone resorption; Hypoxia-inducible factor-1 alpha (HIF-1α); Rheumatoid arthritis; Microtubule