NO is produced by a group of enzymes (NO Synthase, NOS). It is a pleiotrophic signaling molecule that has an important role in vascular tissue as well as in bone (Moncada et al., 1991). Constitutive NOS (cNOS) produces NO in response to calcium. On the other hand, the inducible form of NOS (iNOS) is produced in large amounts independent of calcium (Moncada et al., 1991). Although cNOS is present in the endothelium lining of the blood vessels and osteocytes, iNOS can be induced in the endothelium, VSMC, inflammatory cells, osteocytes, and chondrocytes (Hukkanen et al., 1995). By producing NO, cNOS responds to a variety of physiological stimulation including shear stress, mechanical loading, estrogen, and statins, as well as growth factors (Muniyappa et al., 2000). NO has a protective effect on both bone and vascular tissues (Moncada et al., 1991). Among the atheroprotective effects of NO are the inhibition of VSMC proliferation, platelet aggregation, and cell adhesion. On the other hand, cNOS deficiency in mice leads to hypertension and endothelial dysfunction, reduced bone mineral density (BMD), and osteoblastic number and function. Mice with cNOS deficiency lost bone following ovariectomy, and there was a significantly blunted anabolic response to high-dose exogenous estrogen (Armour et al., 2001). These findings suggest a critical role for NO in regulating bone mass and bone turnover. These findings are also consistent with the results of a clinical trial, where nitroglycerine, a NO donor, was shown to be as effective as estrogen in preventing bone loss associated with surgically induced menopause, when given in a randomized controlled fashion (Wimalawnsa et al., 2000). In contrast to these findings in a mouse model of inflammation-induced bone loss, rapid release and high concentration of NO inhibited proliferation and induced apoptosis of osteoblasts (Mancini et al., 2000). Slow and moderate release of NO however, stimulated the replication of primary rat osteoblasts and alkaline phosphatase activity (Mancini et al., 2000). These findings suggest the presence of both stimulatory and apoptosis-inducing effects of NO on primary osteoblasts (see Figure 58.1). Furthermore, in chronic inflammatory conditions such as rheumatoid arthritis, associated with elevated cytokines and high NO levels, inhibition of NO production reversed bone loss (Sakurai et al., 1995). These findings indicate that in bone and in vascular tissues, the biological response to NO is dose-dependent. Deficiency of cNOS accelerates both osteoporosis and atherosclerosis, and iNOS increases bone loss (Mancini et al., 2000; Sakurai et al., 1995).
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