Defective bone formation and anabolic response to exogenous estrogen in mice with targeted disruption of endothelial nitric oxide synthase

Nitric oxide (NO) is a pleiotropic signaling molecule that is produced by b one cells constitutively and in response to diverse stimuli such as proinfl ammatory cytokines, mechanical strain, and sex hormones. Endothelial nitric oxide synthase (eNOS) is the predominant NOS isoform expressed in bone, bu t its physiological role in regulating bone metabolism remains unclear. Her e we studied various aspects of bone metabolism in female mice with targete d disruption of the eNOS gene. Mice with eNOS deficiency (eNOS KO) had redu ced bone mineral density, and cortical thinning when compared with WT contr ols and histomorphometric analysis of bone revealed profound abnormalities of bone formation, with reduced osteoblast numbers, surfaces and mineral ap position rate. Studies in vitro showed that osteoblasts derived from eNOS K O mice had reduced rates of growth when compared with WT and were less well differentiated as reflected by lower levels of alkaline phosphatase activi ty. Mice with eNOS deficiency lost bone normally following ovariectomy but exhibited a significantly blunted anabolic response to high dose exogenous estrogen. We conclude that the eNOS pathway plays an essential role in regu lating bone mass and bone turnover by modulating osteoblast function.