The Michael Mason Prize Essay 1997. Nitric oxide and bone: what a gas!

Nitric oxide (NO) is an important signalling molecule in bone which is produced in response to diverse stimuli such as pro-inflammatory cytokines, mechanical strain and sex hormones. Recent work suggests that NO exerts biphasic effects on bone cell activity: high concentrations of NO inhibit bone resorption by inhibiting osteoclast formation and by inhibiting the resorptive function of mature osteoclasts, whereas lower NO concentrations potentiate cytokine-induced bone resorption and may be essential for normal osteoclast function. Similarly, growth and differentiation of osteoblasts are inhibited by high concentrations of NO which may partly be responsible for the inhibitory effects of pro-inflammatory cytokines on bone formation. In contrast, lower amounts of NO produced by constitutive nitric oxide synthase (NOS) enzymes may play a role in regulating normal osteoblast growth and in mediating the effects of oestrogens on bone formation. Evidence of inducible nitric oxide synthase (iNOS) expression has been found in the rheumatoid joint and patients with active rheumatoid arthritis (RA) have raised levels of NO breakdown products in blood and urine. This indicates that NO may be involved in the pathogenesis of bone disease and tissue damage associated with inflammatory conditions such as RA, and raises the possibility that iNOS inhibitors may be of therapeutic value in this situation. The observation that both oestrogen and mechanical strain increase NO production by activating constitutive NOS further suggests that bone loss associated with oestrogen deficiency and immobilization may be related to production of NO and may hence be amenable to treatment with pharmacological NO donors.