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 bone cells constitutively and in response to diverse stimuli such as proinflammatory cytokines, mechanical strain, and sex hormones. Endothelial nitric oxide synthase (eNOS) is the predominant NOS isoform expressed in bone, but its physiological role in regulating bone metabolism remains unclear. Here we studied various aspects of bone metabolism in female mice with targeted disruption of the eNOS gene. Mice with eNOS deficiency (eNOS KO) had reduced bone mineral density, and cortical thinning when compared with WT controls and histomorphometric analysis of bone revealed profound abnormalities of bone formation, with reduced osteoblast numbers, surfaces and mineral apposition rate. Studies in vitro showed that osteoblasts derived from eNOS KO mice had reduced rates of growth when compared with WT and were less well differentiated as reflected by lower levels of alkaline phosphatase activity. Mice with eNOS deficiency lost bone norma...

[1]  S. Ralston,et al.  Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[2]  D. Reid,et al.  Evidence for a Pathogenic Role of Nitric Oxide in Inflammation‐Induced Osteoporosis , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[3]  S. Ralston,et al.  Expression and functional role of nitric oxide synthase isoforms in human osteoblast-like cells. , 1999, Bone.

[4]  J. Tobias,et al.  High‐Dose Estrogen Induces De Novo Medullary Bone Formation in Female Mice , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[5]  E H Burger,et al.  Nitric oxide response to shear stress by human bone cell cultures is endothelial nitric oxide synthase dependent. , 1998, Biochemical and biophysical research communications.

[6]  T Jämsä,et al.  Comparison of three-point bending test and peripheral quantitative computed tomography analysis in the evaluation of the strength of mouse femur and tibia. , 1998, Bone.

[7]  J. Chow,et al.  Nitric oxide synthase expression in bone cells. , 1998, Bone.

[8]  R. Pacifici.  Editorial: Cytokines, Estrogen, and Postmenopausal Osteoporosis-The Second Decade. , 1998, Endocrinology.

[9]  H. Bidmon,et al.  Coronary hemodynamics in endothelial NO synthase knockout mice. , 1998, Circulation research.

[10]  S. Ralston,et al.  Estrogen upregulates endothelial constitutive nitric oxide synthase expression in human osteoblast-like cells. , 1998, Endocrinology.

[11]  I. Owan,et al.  Effects of nitric oxide synthase inhibitors on bone formation in rats. , 1997, Bone.

[12]  R. Kimble,et al.  The Functional Block of TNF but Not of IL‐6 Prevents Bone Loss in Ovariectomized Mice , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[13]  S. Ralston,et al.  Mechanisms of cytokine induced bone resorption: role of nitric oxide, cyclic guanosine monophosphate, and prostaglandins. , 1996, Bone.

[14]  L. Donahue,et al.  Genetic variability in adult bone density among inbred strains of mice. , 1996, Bone.

[15]  H. Tsukahara,et al.  Effect of nitric oxide synthase inhibitors on bone metabolism in growing rats. , 1996, The American journal of physiology.

[16]  C. Yallampalli,et al.  Nitric oxide donor alleviates ovariectomy-induced bone loss. , 1996, Bone.

[17]  G. Murrell,et al.  Nitric oxide inhibitor L-NAME suppresses mechanically induced bone formation in rats. , 1996, The American journal of physiology.

[18]  P. Nijweide,et al.  Pulsating fluid flow increases nitric oxide (NO) synthesis by osteocytes but not periosteal fibroblasts--correlation with prostaglandin upregulation. , 1995, Biochemical and biophysical research communications.

[19]  A. Pitsillides,et al.  Mechanical strain‐induced NO production by bone cells: a possible role in adaptive bone (re)modeling? , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  J. Polak,et al.  Cytokine-stimulated expression of inducible nitric oxide synthase by mouse, rat, and human osteoblast-like cells and its functional role in osteoblast metabolic activity. , 1995, Endocrinology.

[21]  P. W. Johnston,et al.  Nitric oxide: A cytokine‐induced regulator of bone resorption , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[22]  J M Polak,et al.  Bidirectional regulation of osteoclast function by nitric oxide synthase isoforms. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Riancho,et al.  Expression and functional role of nitric oxide synthase in osteoblast‐like cells , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[24]  R. Jilka,et al.  Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. , 1995, The New England journal of medicine.

[25]  S. Ralston,et al.  Human osteoblast-like cells produce nitric oxide and express inducible nitric oxide synthase. , 1994, Endocrinology.

[26]  I. Charles,et al.  Induction of calcium-dependent nitric oxide synthases by sex hormones. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[27]  T. Kasten,et al.  Potentiation of osteoclast bone-resorption activity by inhibition of nitric oxide synthase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[28]  P. Nibbering,et al.  Inducible production of nitric oxide in osteoblast-like cells and in fetal mouse bone explants is associated with suppression of osteoclastic bone resorption. , 1994, The Journal of clinical investigation.

[29]  M. Lantry,et al.  High‐dose estrogen inhibits bone resorption and stimulates bone formation in the ovariectomized mouse , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[30]  D. Peterson,et al.  The non specificity of specific nitric oxide synthase inhibitors. , 1992, Biochemical and biophysical research communications.

[31]  H. Datta,et al.  Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Barbagallo,et al.  Histological evidence of increased turnover in bone from spontaneously hypertensive rats. , 1991, Cardioscience.

[33]  E. Ritz,et al.  Hyperparathyroidism and abnormal calcitriol metabolism in the spontaneously hypertensive rat. , 1989, Hypertension.

[34]  A. Parfitt.  Bone histomorphometry: standardization of nomenclature, symbols and units (summary of proposed system). , 1988, Bone.

[35]  M. Drezner,et al.  Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee , 1987, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[36]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[37]  R. Pacifici.  Cytokines, estrogen, and postmenopausal osteoporosis--the second decade. , 1998, Endocrinology.

[38]  J. Pollock,et al.  Expression of Nitric Oxide Synthase Isoforms in Bone and Bone Cell Cultures , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[39]  J. Poser,et al.  Production of osteocalcin by human bone cells in vitro. Effects of 1,25(OH)2D3, 24,25(OH)2D3, parathyroid hormone, and glucocorticoids. , 1984, Metabolic bone disease & related research.