Hypoxia stimulates osteoclast formation from human peripheral blood.
Active pathological bone destruction in humans often occurs in locations where oxygen tension (pO(2)) is likely to be low, for example, at the sites of tumours, inflammation, infections and fractures, or the poorly vascularized yellow fatty marrow of the elderly. We examined the effect of pO(2) on formation of osteoclasts, the cells responsible for bone resorption, in 14-day cultures of normal human peripheral blood mononuclear cells (hPBMCs) on ivory discs. Hypoxia (1-2% O(2)) caused threefold increases in the number of osteoclasts formed, compared with 20% O(2). Hypoxia also caused a twofold increase in the number of nuclei per osteoclast, leading to stimulations of resorption pit formation of up to 10-fold. Exposure to hypoxia led to stabilization of the hypoxia-inducible factors, HIF1alpha and HIF2alpha, and upregulation of vascular endothelial growth factor and interleukin-6 expression by hPBMCs. These findings help explain why extravasation of mononuclear precursors into relatively O(2)-deficient bone microenvironments could result in osteoclast formation and suggest a new mechanism for the bone loss associated with the pathophysiological conditions where hypoxia commonly occurs.
Utting
Jennifer C
JC
Department of Cell and Developmental Biology, University College London, London, UK.
Flanagan
Adrienne M
AM
Brandao-Burch
Andrea
A
Orriss
Isabel R
IR
Arnett
Timothy R
TR
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001862:Bone Resorption / Q000378:metabolism; D015687:Cell Hypoxia; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human