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

Hypoxia and the hypoxia‐inducible factor (HIF) transcription factor regulate angiogenic‐os‐teogenic coupling and osteoclast‐mediated bone resorption. To determine how HIF might coordinate osteoclast and osteoblast function, we studied angiopoi‐etin‐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 osteo‐blasts. ANGPTL4 protein was observed by immunofluorescence in osteoclasts and osteoblasts in vivo. Nor‐moxic inducers of HIF (CoCl 2 , desferrioxamine, and l ‐mimosine) and 100 ng/ml ANGPTL4 stimulated os‐teoclastic 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.—Knowles, H. J., Cleton‐Jansen, A.‐M., Korsching, E., and Athanasou, N.A. Hypoxia‐inducible factor regulates osteoclast‐mediated bone resorption: role of angiopoietin‐like 4. FASEB J. 24, 4648–4659 (2010). www.fasebj.org