Abstract
BackgroundOsteoarthritis (OA) is a debilitating, progressive joint disease.MethodsSimilar to the disease progression in humans, sequential events of early cartilage degradation, subchondral osteopenia followed by sclerosis, and late osteophyte formation were demonstrated in the anterior cruciate ligament transection (ACLT) or ACLT with partial medial meniscectomy (ACLT + MMx) rat OA models. We describe a reliable and consistent method to examine the time dependent changes in the gene expression profiles in articular cartilage and subchondral bone.ResultsLocal regulation of matrix degradation markers was demonstrated by a significant increase in mRNA levels of aggrecanase-1 and MMP-13 as early as the first week post-surgery, and expression remained elevated throughout the 10 week study. Immunohistochemistry confirmed MMP-13 expression in differentiated chondrocytes and synovial fibroblasts at week-2 and cells within osteophytes at week-10 in the surgically-modified-joints. Concomitant increases in chondrocyte differentiation markers, Col IIA and Sox 9, and vascular invasion markers, VEGF and CD31, peaked around week-2 to -4, and returned to Sham levels at later time points in both models. Indeed, VEGF-positive cells were found in the deep articular chondrocytes adjacent to subchondral bone. Osteoclastic bone resorption markers, cathepsin K and TRAP, were also elevated at week-2. Confirming bone resorption is an early local event in OA progression, cathepsin K positive osteoclasts were found invading the articular cartilage from the subchondral region at week 2. This was followed by late disease events, including subchondral sclerosis and osteophyte formation, as demonstrated by the upregulation of the osteoanabolic markers runx2 and osterix, toward week-4 to 6 post-surgery.ConclusionsIn summary, this study demonstrated the temporal and cohesive gene expression changes in articular cartilage and subchondral bone using known markers of OA progression. The findings here support genome-wide profiling efforts to elucidate the sequential and complex regulation of the disease.
Highlights
Osteoarthritis (OA) is a debilitating, progressive joint disease
Because the subchondral bone is critically important in containing the mechanical abnormalities that damage the cartilage, emphasis on a panel of biomarkers of bone remodeling resulting from the abnormal stresses on the joint has been proposed as diagnostic tools used to monitor treatment responses to potential structure-modifying drugs [13,14]
Collection of articular cartilage and subchondral bone from the surgically induced joint instability models in the rats In this study, we initially focused on developing a reliable method for serially collecting the articular cartilage and subchondral bone, the epiphyseal and metaphyseal bone slices from the tibeal plateaux of surgically modified and contra-lateral sham-operated joints for RNA processing
Summary
Osteoarthritis (OA) is a debilitating, progressive joint disease. Osteoarthritis (OA) is a joint disease that involves degeneration of cartilage, limited synovitis, subchondral bone changes, and osteophyte formation [1]. Epidemiologic studies have correlated both the increases in bone mineral density and in the rate of bone turnover, as determined by biochemical markers, with increases in the incidence and severity of osteoarthritis [10,11,12]. Because the subchondral bone is critically important in containing the mechanical abnormalities that damage the cartilage, emphasis on a panel of biomarkers of bone remodeling resulting from the abnormal stresses on the joint has been proposed as diagnostic tools used to monitor treatment responses to potential structure-modifying drugs [13,14]. The mechanical and biochemical properties of the subchondral bone are of particular interest in any attempt to determine the molecular mechanisms responsible for initiating osteoarthritis
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