The Many Roles of NO

In the review article “Molecular Aspects of Pathogenesis in Osteoarthritis: The Role of Inflammation” I found several tidbits interesting. In osteoarthritis , the inflammation factor is actually very low compared to other forms of arthritis however IL-1 and TNF-α have been found in the synovial fluid of osteoarthritis (OA) patients. While the cause of OA is unknown, one idea is that the loss (decreased synthesis) of proteoglycans (PG) leads to a decrease in water retention of the cartilage and consequently less fluidity and resilience of the cartilage.

In the article the relationship between Insulin-like Growth Factor-I and PG synthesis is explored. I found it interesting that IGF-I had a vast majority of roles and according to the article IGF-I was responsible for stimulating PG synthesis and that “particularly high levels of expression are shown by cells within areas of more advanced OA lesions”. This would make one wonder if the body is compensating by increasing IGF-I expression in affected areas why the disease was still having an effect. The paper presented the theory that IGF-I had a lessened effect on articular chrondocytes possibly due to an “upregulation of IGF-binding proteins” (Hedbom and Hauselmann 46).

A science article online shed further light on that theory. The presence of elevated levels of both IGF and IGF-binding proteins (IGF-BPs) in the synovial fluid of both RA and OA patients has inspired the hypothesis that an imbalance of these elements causes the insensitivity. IGF-BPs “act as transport proteins in plasma, prolong the half-life of IGF, provide a means of tissue localization for IGF, modulate interaction of IGF with its receptors, and, in some cases, have IGF-I independent effects on cells. Thus the maintenance of IGF actions on chrondocytes is complicated by regulation of and by IGFBPs and the proteases that degrade IGFBPs and therefore indirectly affect responses to IGF-I” (Studer, Levicoff, Georgescu et al.).

Another part of the article addressed the role of NO in arthritis not only as an element responsible for cartilage damage via inflammation and inhibition of PG and collagen synthesis in conjunction with IL-1 and other cytokines but also as one of the responsible parties for “cartilage insentivity to IGF-I.” (Studer, Levicoff, Georgescu et al.) The role of NO was suggested by an experiment with arthritis induced mice in which wild-type mice showed the expected IGF-I insensitivity but the second group had iNOS (the enzyme responsible for the production o f NO) knocked out and that showed an ability to increase PG in response to IGF-I. That led to the experiment design in the paper:

“The current studies were designed to 1) determine whether chondrocyte insensitivity to IGF-I could be observed in an in vitro system, and if so, 2) utilize cartilage and chondrocytes in culture to begin an analysis of the mechanisms by which NO causes unresponsiveness to IGF-I. We used lapine cartilage and chondrocytes in organ and monolayer culture and found that exposure to NO inhibits the IGF-I-stimulated increase in proteoglycan synthesis. This is seen with NO produced exogenously from the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate] (DETA NONOate) or endogenously following IL-1 stimulation or adenoviral transfer of iNOS (Ad-iNOS) into chondrocytes. This effect of NO is reversible. Relevance to human disease is implied, as inhibition of NO synthesis with NG-monomethyl-L-arginine (L-NMA) during in vitro organ culture of human articular cartilage recovered from OA joints restores a brisk anabolic response to IGF-I. IGF-I-stimulated tyrosine phosphorylation of the IGF-I receptor is decreased by prior exposure of chondrocytes to NO, suggesting that chondrocyte insensitivity to IGF-I in the presence of NO is due at least in part to an action of NO on this step in the signal transduction pathway” (Studer, Levicoff, Georgescu et al.).

In conclusion the paper described how NO was partially responsible for chondrocyte insentivity to IGF-I due to the inhibition of receptor autophosphorylation, which is an integral part of IGF-I receptor (Tyrosine Kinase) functionality. Therefore the disruption of this mechanism is one hypothesis to explain the insensitivity of arthritic cartilage to IGF-I.

Nitric oxide inhibits chondrocyte response to IGF-I: inhibition of IGF-IRβ tyrosine phosphorylation
R. K. Studer, E. Levicoff, H. Georgescu, L. Miller, D. Jaffurs, and C. H. Evans
http://ajpcell.physiology.org/cgi/content/full/279/4/C961