Nitric oxide and bone

Nitric oxide (NO) is a free radical which has important effects on bone cel l function. The endothelial isoform of nitric oxide synthase (eNOS) is wide ly expressed in bone on a constitutive basis, whereas inducible NOS is only expressed in response to inflammatory stimuli. It is currently unclear whe ther neuronal NOS is expressed by bone cells, pro-inflammatory cytokines su ch as IL-1 and TNF cause activation of the iNOS pathway in bone cells and N O derived from this pathway potentiates cytokine and inflammation induced b one loss. These actions of NO are relevant to the pathogenesis of osteoporo sis in inflammatory diseases such as rheumatoid arthritis, which are charac terized by increased NO production and cytokine activation. Interferon gamm a is a particularly potent stimulator of NO production when combined with o ther cytokines, causing very high concentrations of NO to be produced. Thes e high levels of NO inhibit bone resorption and formation and may act to su ppress bone turnover in severe inflammation. The eNOS isoform seems to play a key role in regulating osteoblast activity and bone formation since eNOS knockout mice have osteoporosis due to defective bone formation. Other stu dies have indicated that the NO derived from the eNOS pathway acts as a med iator of the effects of oestrogen in bone. eNOS also mediates the effects o f mechanical loading on the skeleton where it acts along with prostaglandin s, to promote bone formation and suppress bone resorption. Pharmacological NO donors have been shown to increase bone mass in experimental animals and preliminary evidence suggests that these agents may also influence bone tu rnover in man. These data indicate that the L-arginine/NO pathway represent s a novel target for therapeutic intervention in the prevention and treatme nt of bone diseases.