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However, HIF also enhances the bone\u2010resorbing activity of mature osteoclasts. It is therefore essential to determine the full effect(s) of HIF on both the formation and the bone\u2010resorbing function of osteoclasts in order to understand how they might respond to such a strategy. Expression of <jats:italic>HIF\u20101\u03b1<\/jats:italic> mRNA and protein increased during osteoclast differentiation from CD14+ monocytic precursors, additionally inducing expression of the HIF\u2010regulated glycolytic enzymes. However, <jats:italic>HIF\u20101\u03b1<\/jats:italic> siRNA only moderately affected osteoclast differentiation, accelerating fusion of precursor cells. HIF induction by inhibition of the regulatory prolyl\u20104\u2010hydroxylase (PHD) enzymes reduced osteoclastogenesis, but was confirmed to enhance bone resorption by mature osteoclasts. <jats:italic>Phd2<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup> murine osteoclasts also exhibited enhanced bone resorption, associated with increased expression of resorption\u2010associated <jats:italic>Acp5<\/jats:italic>, in comparison with wild\u2010type cells from littermate controls. <jats:italic>Phd3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> bone marrow precursors displayed accelerated early fusion, mirroring results with <jats:italic>HIF\u20101\u03b1<\/jats:italic> siRNA. <jats:italic>In vivo<\/jats:italic>, <jats:italic>Phd2<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup> and <jats:italic>Phd3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice exhibited reduced trabecular bone mass, associated with reduced mineralization by <jats:italic>Phd2<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup> osteoblasts. These data indicate that HIF predominantly functions as a regulator of osteoclast\u2010mediated bone resorption, with little effect on osteoclast differentiation. Inhibition of HIF might therefore represent an alternative strategy to treat diseases characterized by pathological levels of osteolysis. \u00a9 2017 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.4906","type":"journal-article","created":{"date-parts":[[2017,4,18]],"date-time":"2017-04-18T06:48:06Z","timestamp":1492498086000},"page":"322-333","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["Hypoxia\u2010inducible factor 1\u2010alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl\u20104\u2010hydroxylase 2"],"prefix":"10.1002","volume":"242","author":[{"given":"Philippa A","family":"Hulley","sequence":"first","affiliation":[{"name":"Nuffield Department of Orthopaedics Rheumatology &amp; Musculoskeletal Sciences University of 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