{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T02:23:00Z","timestamp":1770776580643,"version":"3.50.0"},"reference-count":64,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2008,1,10]],"date-time":"2008-01-10T00:00:00Z","timestamp":1199923200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"EuroBoNeT","award":["LSHC-CT-2006-018814"],"award-info":[{"award-number":["LSHC-CT-2006-018814"]}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2008,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hypoxia is an important regulator of bone biology and stimulates osteoclast differentiation from monocytic precursors. Hypoxia\u2010inducible factor (HIF) is a key pro\u2010tumourigenic transcription factor mediating pathways of hypoxia\u2010inducible gene expression. We have described expression of HIF\u20101\u03b1 and HIF\u20102\u03b1 in the multi\u2010nucleated, osteoclast\u2010like giant cells and the mononuclear stromal component of giant cell tumour of bone (GCTB), a locally osteolytic primary bone tumour. HIF induction was observed in culture in the osteoblastic MG\u201063 cell line, primary GCTB stromal cells, and monocyte\u2010derived osteoclasts following stimulation with hypoxia (0.1% O\n                    <jats:sub>2<\/jats:sub>\n                    ) or the osteoclastogenic cytokines hepatocyte growth factor (HGF) and macrophage colony\u2010stimulating factor (M\u2010CSF). This was accompanied by increased expression of the downstream target genes Bcl\u20102\/adenovirus E1B 19 kD\u2010interacting protein 3 (BNIP3), Glut\u20101, and vascular endothelial growth factor (VEGF). As VEGF can substitute for M\u2010CSF to support osteoclastogenesis in the presence of receptor activator for nuclear factor \u03baB ligand (RANKL), we assessed the effect of MG\u201063 hypoxic conditioned media on osteoclast differentiation. In the presence of RANKL, hypoxic conditioned media induced the formation of active osteoclasts, as assessed from the numbers of TRAP\u2010positive multi\u2010nucleated cells and the area of lacunar bone resorption, which was inhibited by co\u2010incubation with a neutralizing anti\u2010VEGF antibody. Targeted siRNA ablated HIF\u20101\u03b1 and\/or HIF\u20102\u03b1 expression in MG\u201063 cells and reduced hypoxic secretion of VEGF. Hypoxic conditioned media from cells treated with siRNA for (HIF\u20101\u03b1 + HIF\u20102\u03b1) produced a significant decrease in osteoclast number (\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.005) and activity (\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.05) in comparison with the scrambled siRNA control. These results suggest that local hypoxia could indirectly influence osteoclastogenesis via autocrine and paracrine secretion of VEGF under the control of HIF. This is potentially an important mechanism of pathogenesis for GCTB and other osteolytic lesions. Copyright \u00a9 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.\n                  <\/jats:p>","DOI":"10.1002\/path.2319","type":"journal-article","created":{"date-parts":[[2008,2,7]],"date-time":"2008-02-07T08:16:19Z","timestamp":1202372179000},"page":"56-66","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["Hypoxia\u2010inducible factor is expressed in giant cell tumour of bone and mediates paracrine effects of hypoxia on monocyte\u2013osteoclast differentiation via induction of 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