Risk factors for primary OA include increasing age, history of injury to the joint (trauma, repetitive stress, inflammation, etc.), and obesity. Secondary OA can develop as a result of any physical, metabolic, or chemical injury to the joint such as congenital or developmental bone malformations (Legg-Calve-Perthes disease or SCFE), metabolic diseases (alcaptonuria, hemochromatosis, Wilson’s disease), endocrine (acromegaly, hyperparathyroidism, DM, hypothyroidism), abnormal calcium deposition (calcium pyrophosphate dihydrate deposition, apatitie arthropathy), other bone/joint diseases (AVN, RA, gout, infection), neuropathic (Charcot joints), and even such entities as frostbite, Caisson’s disease, and hemoglobinopathies.
The details of genetics of OA are unknown at this time. There is, however, a significant genetic component. Spector et al. showed in 1996 in a classic female twin study that there was higher incidence of radiographic OA of hands and knees in identical twins than non-identical twins. Overall genetic influence on radiographic OA of hands and knees in women was estimated at 39-65%, independent of known environmental or demographic factors. Demissie and colleagues took the Framingham Heart Study cohort and their offspring and tried to establish a genetic linkage of hand OA. They used LOD scores to establish the linkage based on the radiographic evidence and found evidence for presence of hand OA susceptibility genes on chromosomes 7, 9, 13, and 19. Similar studies suggest loci in areas of chromosomes 2q for susceptibility to nodal OA and llq for female-specific susceptibility to severe hip or knee OA. Further investigations are needed to confirm these linkages and determine the exact genes. buy kamagra tablets
ETIOLOGY AND PATHOPHYSIOLOGY
Despite the high prevalence and morbidity of primary OA, the cause is still unknown. The prevailing thought is that the imbalance in the joint loading or excessive joint loading causes the initial damage that slowly progresses. Numerous studies have uncovered the changes in biochemical, cellular, and metabolic processes in the osteoarthritic joint cartilage. The general pathologic changes include softening and focal disintegration of the articular cartilage and the formation of osteophytes at the joint margins leading to joint pain and deformation. It has been shown that the water content of an osteoarthritic joint is increased due to the weakening of the collagen network, which normally prevents the highly hyrophilic proteoglycans from absorbing too much water. Type IX collagen, which is normally present in the joint cartilage, is thought to “glue” the main type II collagen fibers together and prevent their slippage over each other. Collagen analysis in the osteoarthritic joint shows marked decrease in type IX collagen content, which could explain the weakening of the collagen network. In addition, the concentration of proteoglycans falls sharply with advancing age and may decrease by over 50%.
The metabolic changes affecting the joint in OA include an increase in synthesis and secretion by chondrocytes of active matrix-degrading enzymes, such as stromelysin and collagenase. These enzymes are able to break down all of the components of the extracellular matrix and rapidly degrade the articular cartilage. Such derangement in the joint cartilage structure and metabolic state is thought to be due to activation of chondrocytes by increased levels of interleukin-I (IL-1) to produce matrix-degrading enzymes. At the same time there is a decrease in the concentration of the substances such as TIMP-1, TIMP-2, and PAI-1 that are inhibitory to the metalloproteases stromyelisin and collagenase. It is not known why the IL-1 level increases while TIMP and PAI levels decrease. The overall result is gradual but irreversible degradation of the artricular cartillage, formation of osteophytes, and subsequent pain and deformity.
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The key question is why and how this process begins. The data is very limited due to the inability to study the early asymptomatic phase of disease in humans. All of the existing data is based on secondary osteoarthritis in animal models. The first alteration seems to be an increase in water content of the cartilage—indicating weakening of the collagen network as described above. This is followed by initial increase in proteoglycan content but eventual decrease below the baseline.
This, in turn, leads to loss of compressive stiffness and elasticity and an increase in water permeability (improving diffusion of degradative enzymes).
Another insight given by the research in animal models of OA is the importance of the inflammatory component, which was previously thought to be only a secondary phenomenon. IL-1 plays the key role, as mentioned above. TNF-alpha also seems to play a significant role. Both cytokines upregulate production of metalloproteinases, as well as blunt the chondrocytes’ mechanisms for the extracellular matrix repair. Further exacerbating the metabolic picture is the fact that the IL-1 receptors are upregulated in the OA tissues and that the production on the IL-1 receptor antagonists is decreased, making the cytokine even more effective at cartilage degradation.