Department of Cell and Developmental Biology, University College London, London, UK.
Cell Biochem Funct. 2010 Jul;28(5):374-80. doi: 10.1002/cbf.1660.
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.
在人类中，病理性骨破坏通常发生在氧气张力（pO(2)）可能较低的部位，例如肿瘤、炎症、感染和骨折部位，或老年人的血管化不良的黄色脂肪骨髓。我们研究了 pO(2)对正常人外周血单核细胞（hPBMC）在象牙盘上培养 14 天形成破骨细胞（负责骨吸收的细胞）的影响。与 20% O(2)相比，缺氧（1-2% O(2))导致形成的破骨细胞数量增加了三倍。缺氧还导致每个破骨细胞的细胞核数量增加了两倍，导致吸收坑的形成刺激增加了高达 10 倍。暴露于缺氧会导致缺氧诱导因子 HIF1alpha 和 HIF2alpha 的稳定，并上调 hPBMC 的血管内皮生长因子和白细胞介素-6 的表达。这些发现有助于解释为什么单核细胞前体外渗到相对缺氧的骨微环境中会导致破骨细胞的形成，并为与缺氧常见的病理生理状况相关的骨丢失提供了新的机制。
