NITRIC-OXIDE AND ITS ROLE IN ORTHOPEDIC DISEASE

Nitric oxide ( NO) is synthesized by the enzyme nitric oxide synthase (NOS). There are 2 constitutive forms of NOS (cNOS) and 1 inducible fo rm (iNOS). Cells containing cNOS rapidly and transiently produce small amounts of .NO in response to agonists that raise cytosolic levels of free Ca2+, whereas cells expressing inducible iNOS produce large amou nts of NO for extended periods after a lag of several hours during whi ch time the enzyme is induced. Until recently, the 2 constitutive isof orms of NOS were thought to be confined to endothelial cells (eNOS) an d brain (bNOS or nNOS). However, eNOS and bNOS have been identified in an increasing variety of additional cells. Many, if not most, types o f cells are capable of expressing iNOS in response to cytokines, endot oxin, and phagocytosis. Regulation of iNOS occurs at transcriptional, translational, and posttranslational levels. Because .NO is rapidly di ffusible and soluble in hydrophobic and aqueous environments, it is we ll suited to its role as an intercellular messenger with the unique ab ility to penetrate solid tissue. However, it is rapidly inactivated by hemoglobin. The biochemistry of.NO is dominated by its rapid reaction with oxygen and transitional metals, notably iron. The former reactio n may be protective, as when neutralizing superoxide (.O-2(-)), or har mful in forming additional highly damaging radicals such as peroxynitr ite. Interaction of .NO with iron-containing proteins has a number of sequelae, including the activation of guanylate cyclase, inhibition of mitochondrial respiration, and inhibition of cell division. Nitric ox ide has been implicated in a number of conditions of orthopaedic inter est, including inflammation, arthritis, osteoporosis, sepsis, ligament healing, and aseptic loosening of joint prostheses.