Journal
FASEB JOURNAL
Volume 24, Issue 12, Pages 4648-4659Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.10-162230
Keywords
osteoblast; proliferation; differentiation; osteoclastogenesis; pathological bone resorption
Categories
Funding
- EuroBoNeT
- European Commission [LSH-CCT-2006-018 814]
- Arthritis Research UK [MP/19200]
- Oxford National Institute Health Research Biomedical Research Unit (NIHR BRU)
- German Bundesministerium fur Bildung und Forschung [01GM0869]
- Versus Arthritis [19200] Funding Source: researchfish
Ask authors/readers for more resources
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 (CoCl2, 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-1 alpha 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-1 alpha 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
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available