Morphological and molecular changes in developing guinea pig osteoarthritis

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Surgical Science

Sammanfattning: Osteoarthritis (OA)-an unspecific term for late joint destruction-is one of the most common causes of pain and disability in elderly. OA is characterized by destruction of articular cartilage and insufficient tissue repair. Hartley guinea pigs develop a spontaneous knee arthropathy similar to primary human knee OA. The lesions progress slowly with age and increasing body weight, first occurring in the non-meniscus covered part of the medial tibial condyle. Load redistribution by vaIgus femoral osteotomy and amputation retards development on surfaces with decreased load, while surfaces with increased load show a more progressive OA pattern. Biochemical changes are unevenly distributed depending on distance from the articular surface as well as distance from the cells. In study I we used gold-labeled antibodies directed towards chondroitin4- sulfate, a proteoglycan (PG) constituent in cartilage, to analyze variations in PG concentration at different sites. The PG concentration decreased in the upper zones of cartilage developing overt OA, while it increased in deeper zones. Cartilage with advanced OA had lower PG concentration in the upper zones than non-OA cartilage of the same age. In study II we analyzed the effect of load redistribution, e.g. below knee amputation and vaIgus femoral osteotomy, on PG and collagen concentrations. Increased load was followed by decreased cartilage PG concentration whereas decreased load resulted in increased concentration, indicating a cell-mediated process with parallel biochemical and morphological patterns. The importance of load was further investigated in study III by analyzing the effects of body weight and exercise. Animals were allocated to three groups: controls living under standard laboratory conditions with food ad libitum; mobilized animals with unrestricted motion in a large room with food ad libitum; and a diet group weight-matched with the mobilized group. The diet and mobilized animals had a 30-40% lower bodyweight than controls. The mobilized animals tended to have the least severe lesions at 9 months. At 12 months, lesions had progressed in mobilized and control animals, being most severe in mobilized animals. Lesions were stationary in diet animals. Thus, body mass reduction appears to retard OA progression in animals mainly subjected to a static load, but not sufficiently in animals with a more dynamic load. Dynamic load is perhaps chondroprotective in the early phase but harmful in later stages. To identify early events in guinea pig OA we sequentially studied cartilage morphology, hydration and PG concentration in young guinea pigs (study IV). We found an age-related decreased hydration and PG concentration in OA as well as non-OA cartilage, but higher PG concentration and hydration in the medial condyle (OA) than in the lateral condyle (non-OA). The overall decreased hydration and PG concentration probably represent maturation while the difference between condyles may be a compensatory reaction to higher load. Interactions between the collagen II fibers are considered to involve cartilage matrix proteins such as fibronectin and cartilage oligomeric matrix protein (COMP). In study V we analyzed the incorporation of labeled S04 and leucine in newly synthesized cartilage matrix proteins and the cartilage concentration of COMP and fibronectin. We found increased synthesis and concentration of fibronectin and a presumed increased turnover of COMP in OA cartilage, hypothetically reflecting repair mechanisms to maintain cartilage integrity. The integrity of the superficial layer seems to be crucial to withstand further destruction of articular cartilage. A constant morphological pattern in the studies presented in this thesis was early cell depletion in the superficial zone parallel with fibrillation associated with metabolic changes, e.g. altered concentrations of proteoglycans and matrix proteins, indicating a cell-mediated process.

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