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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.

Type

Journal article

Journal

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Publication Date

12/2010

Volume

24

Pages

4648 - 4659

Addresses

Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington, Oxford, OX3 7LD, UK. helen.knowles@ndorms.ox.ac.uk

Keywords

Cells, Cultured, Cell Line, Osteoclasts, Humans, Bone Resorption, Angiopoietins, RNA, Small Interfering, Blotting, Western, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Polymerase Chain Reaction, Cell Differentiation, Cell Proliferation, Hypoxia-Inducible Factor 1, alpha Subunit