Hypoxic downregulation of cellular proliferation and loss of phenotype stability in human osteoblasts is mediated by HIF-1α
Hypoxic downregulation of cellular proliferation and loss of phenotype stability in human osteoblasts is mediated by HIF-1α
复制标题
DOI：
10.3233/ch-2011-1478
复制
发表时间：
2011-01-01
影响因子：
2.1
通讯作者：
Grifka, Joachim
中科院分区：
文献类型：
--
作者：
Lechler, Philipp;Klein, Silvan M.;Grifka, Joachim
Both, skeletal development and fracture healing depend on an orchestrated sequence of cellular growth and differentiation processes. Regional changes in tissue oxygen tension were proposed as key regulators of osteoblast proliferation and phenotype. Hypoxia results in the stabilization of hypoxia-inducible factor-1 alpha (HIF-1 alpha), thus influencing expression of a multitude of genes required for cellular adaptation. In the present study we dissected the effects of HIF-1 alpha on cellular proliferation and gene expression of primary human osteoblasts.Primary human osteoblasts were studied by transfecting siRNA and plasmids coding for human HIF-1 alpha. Gene expression was analyzed by western blot and quantitative PCR. Functional assays were performed to study HIF-1 alpha function, i.e. proliferation and cell cycle analysis.As previously reported exposure to hypoxia led to a stabilization of HIF-1 alpha on protein level and resulted in reduced rates of proliferation and osteocalcin expression. Furthermore, the expression of the proproliferative gene survivin was significantly reduced (p < 0.01). Knock down of HIF-1 alpha attenuated hypoxic downregulation of proliferation (p < 0.05), and osteocalcin (p < 0.05) as well as survivin (p < 0.05) expression significantly.Importantly, the isolated overexpression of HIF-1 alpha impaired proliferative activity and led to significantly reduced rates of expression of osteocalcin (p < 0.05) and survivin (p < 0.01).The present study shows that HIF-1 alpha might reduce proliferation and survivin expression in primary human osteoblasts independently from cellular hypoxia. Furthermore, HIF-1 alpha promoted the loss of the characteristic osteoblastic marker, osteocalcin in vitro. These findings underline the important role of HIF-1 alpha in bone physiology and pathophysiology. Modulating HIF-1 alpha function in hypoxic environments could be of value for future therapeutic approaches.
