Hypoxia-inducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4.

Journal article

Hypoxia and the hypoxia-inducible factor (HIF) transcription factor regulate angiogenic-osteogenic coupling and osteoclast-mediated bone resorption. To determine how HIF might coordinate osteoclast and osteoblast function, we studied angiopoietin-like 4 (ANGPTL4), the top HIF target gene in an Illumina HumanWG-6 v3.0 48k array of normoxic vs. hypoxic osteoclasts differentiated from human CD14(+) monocytes (14.3-fold induction, P<0.0004). ANGPTL4 mRNA and protein were induced by 24 h at 2% O(2) in human primary osteoclasts, monocytes, and osteoblasts. ANGPTL4 protein was observed by immunofluorescence in osteoclasts and osteoblasts in vivo. Normoxic inducers of HIF (CoCl(2), desferrioxamine, and l-mimosine) and 100 ng/ml ANGPTL4 stimulated osteoclastic resorption 2- to 3-fold in assays of lacunar dentine resorption, without affecting osteoclast viability. Isoform-specific HIF-1α small interfering RNA ablated hypoxic induction of ANGPTL4 and of resorption, which was rescued by addition of exogenous ANGPTL4 (P<0.001). In the osteoblastic Saos2 cell line, ANGPTL4 caused a dose-dependent increase in proliferation (P<0.01, 100 ng/ml) and, at lower doses (1-25 ng/ml), mineralization. These results demonstrate that HIF is sufficient to enhance osteoclast-mediated bone resorption and that ANGPTL4 can compensate for HIF-1α deficiency with respect to stimulation of osteoclast activity and also augments osteoblast proliferation and differentiation.

Authors: Knowles, H; Cleton-Jansen, A; Korsching, E; Athanasou, N

• Publication status: Published
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• Volume: 24
• Issue: 12
• Pages: 4648-4659
• Publication date: 2010-12-01
• DOI: 10.1096/fj.10-162230
• EISSN: 1530-6860
• ISSN: 0892-6638
• Language: English
• Keywords: Cell Line; Polymerase Chain Reaction; Cells, Cultured; Osteoclasts; Humans; Enzyme-Linked Immunosorbent Assay; Bone Resorption; Blotting, Western; Immunohistochemistry; Cell Proliferation; Angiopoietins; RNA, Small Interfering; Cell Differentiation; Hypoxia-Inducible Factor 1, alpha Subunit