Abstract
Loss of glycosaminoglycan (GAG) chains of proteoglycans (PGs) is an early event of osteoarthritis (OA) resulting in cartilage degradation that has been previously demonstrated in both huma and experimental OA models. However, the mechanism of GAG loss and the role of xylosyltransferase-I (XT-I) that initiates GAG biosynthesis onto PG molecules in the pathogenic process of human OA are unknown. In this study, we have characterized XT-I expression and activity together with GAG synthesis in human OA cartilage obtained from different regions of the same joint, defined as “normal”, “late-stage” or adjacent to “late-stage”. The results showed that GAG synthesis and content increased in cartilage from areas flanking OA lesions compared to cartilage from macroscopically “normal” unaffected regions, while decreased in “late-stage” OA cartilage lesions. This increase in anabolic state was associated with a marked upregulation of XT-I expression and activity in cartilage “next to lesion” while a decrease in the “late-stage” OA cartilage. Importantly, XT-I inhibition by shRNA or forced-expression with a pCMV-XT-I construct correlated with the modulation of GAG anabolism in human cartilage explants. The observation that XT-I gene expression was down-regulated by IL-1β and up-regulated by TGF-β1 indicates that these cytokines may play a role in regulating GAG content in human OA. Noteworthy, expression of IL-1β receptor (IL-1R1) was down-regulated whereas that of TGF-β1 was up-regulated in early OA cartilage. Theses observations may account for upregulation of XT-I and sustained GAG synthesis prior to the development of cartilage lesions during the pathogenic process of OA.
Highlights
Osteoarthritis (OA) is a chronic, progressive, degenerative disorder of joint characterized by breakdown of articular cartilage leading to functional failure of the joint
Evidence from studies in vitro and in vivo indicates that interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) are the predominant cytokines involved in the initiation and progression of articular cartilage destruction [4,5]
Previous studies of human OA have compared late OA cartilage obtained from joint replacement surgeries to non-OA cartilage from trauma subjects or at autopsy
Summary
Osteoarthritis (OA) is a chronic, progressive, degenerative disorder of joint characterized by breakdown of articular cartilage leading to functional failure of the joint. OA is characterized by progressive loss of extracellular matrix (ECM) proteins, causing mechanical disruption of the articular cartilage surface, together with subchondral bone sclerosis and osteophyte formation [1]. Numerous studies suggest that most of the biological activity of PGs is mediated by their glycosaminoglycan (GAG) chains. In this context, GAG chains play important roles in growth factor signaling, cellular differentiation, morphogenesis, and pathophysiology [7,8]. Alteration in the capacity of OA chondrocytes to restore the integrity of the cartilage matrix may be due to dysfunction of the regulatory pathway leading to formation of glycosaminoglycan chains
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