Nitric oxide and bone

Abstract

Nitric oxide (NO) is a free radical which has important effects on bone cell function. The endothelial isoform of nitric oxide synthase (eNOS) is widely expressed in bone on a constitutive basis, whereas inducible NOS is only expressed in response to inflammatory stimuli. It is currently unclear whether neuronal NOS is expressed by bone cells. Pro-inflammatory cytokines such as IL-1 and TNF cause activation of the iNOS pathway in bone cells and NO derived from this pathway potentiates cytokine and inflammation induced bone loss. These actions of NO are relevant to the pathogenesis of osteoporosis in inflammatory diseases such as rheumatoid arthritis, which are characterized by increased NO production and cytokine activation. Interferon gamma is a particularly potent stimulator of NO production when combined with other cytokines, causing very high concentrations of NO to be produced. These high levels of NO inhibit bone resorption and formation and may act to suppress 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 studies have indicated that the NO derived from the eNOS pathway acts as a mediator of the effects of oestrogen in bone. eNOS also mediates the effects of mechanical loading on the skeleton where it acts along with prostaglandins, 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 turnover in man. These data indicate that the L-arginine/NO pathway represents a novel target for therapeutic intervention in the prevention and treatment of bone diseases.

Figure 1

The bone remodelling cycle. The bone remodelling cycle of resorption, reversal and bone formation is responsible for renewal and repair of old and damaged bone (main panel). Osteoclasts differentiate from haemopoetic precursors in the monocyte lineage in response to activation of RANK, by its ligand RANKL, expressed on stromal cells (inset). This interaction is blocked by OPG which acts as a decoy receptor for RANKL. Osteoblasts differentiate from mesenchymal precursors in bone marrow in response to activation of the osteoblast-specific transcription factor Cbfa1.

Figure 2

The l-arginine–nitric oxide pathway. NO is synthesized from l-arginine and molecular oxygen by the NOS group of enzymes. In inflammation, cytokines such as IL-1 and TNF are upregulated. The cytokines induce expression of the inducible NOS (iNOS) gene, leading to synthesis of the iNOS enzyme, which produces nitric oxide (NO) from l-arginine. NO can also be produced by pharmacological NO donors such as SNAP. NO is a very reactive molecule and rapidly reacts with oxygen to form nitrite and nitrate.