Abstract
Aging is one of the major pathologic factors associated with osteoarthritis (OA). Recently, numerous reports have demonstrated the impact of sirtuin-1 (Sirt1), which is the NAD-dependent deacetylase, on human aging. It has been demonstrated that Sirt1 induces osteogenic and chondrogenic differentiation of mesenchymal stem cells. However, the role of Sirt1 in the OA chondrocytes still remains unknown. We postulated that Sirt1 regulates a hypertrophic chondrocyte lineage and degeneration of articular cartilage through the activation of osteogenic transcriptional activator Runx2 and matrix metalloproteinase (MMP)-13 in OA chondrocytes. To verify whether sirtuin-1 (Sirt1) regulates chondrocyte activity in OA, we studied expressions of Sirt1, Runx2 and production of MMP-13, and their associations in human OA chondrocytes. The expression of Sirt1 was ubiquitously observed in osteoarthritic chondrocytes; in contrast, Runx2 expressed in the osteophyte region in patients with OA and OA model mice. OA relating catabolic factor IL-1βincreased the expression of Runx2 in OA chondrocytes. OA chondrocytes, which were pretreated with Sirt1 inhibitor, inhibited the IL-1β-induced expression of Runx2 compared to the control. Since the Runx2 is a promotor of MMP-13 expression, Sirt1 inactivation may inhibit the Runx2 expression and the resultant down-regulation of MMP-13 production in chondrocytes. Our findings suggest thatSirt1 may regulate the expression of Runx2, which is the osteogenic transcription factor, and the production of MMP-13 from chondrocytes in OA. Since Sirt1 activity is known to be affected by several stresses, including inflammation and oxidative stress, as well as aging, SIRT may be involved in the development of OA.
Highlights
In osteoarthritis (OA), mechanical and chemical stresses to articular cartilage downregulate chondrocyte activities and induce secretion of catabolic factors, such as proinflammatory cytokines and cartilage degrading enzymes, by chondrocytes [1,2,3,4]
Runx2 was expressed by osteoarthritic chondrocytes from patients with severe OA
Fujita et al reported that overexpression of Sirt1 by gene transfection in chondrocytes inhibited expression of osteoarthritic genes such as matrix metalloproteinase (MMP)-13 [24]. They demonstrated that reduction of Sirt1 by small-interfering RNA caused an increase in MMP-13 production from chondrocytes, suggesting the down-regulatory effect of Sirt1 on the production of MMP-13in chondrocytes. These findings suggest that Sirt1 plays a protective part to suppress IL-1β-induced expression of cartilage degrading enzyme, MMP-13, partially through the NF-kB pathway
Summary
In osteoarthritis (OA), mechanical and chemical stresses to articular cartilage downregulate chondrocyte activities and induce secretion of catabolic factors, such as proinflammatory cytokines and cartilage degrading enzymes, by chondrocytes [1,2,3,4]. They examined different biomarkers of cellular aging in human articular cartilage tissues and found that chondrocyte senescence correlated with donor aging Their findings clearly demonstrate that the association between OA and aging is due, at least in part, to the age-related decrease of chondrocytes and cartilage matrix function with aging. It has been demonstrated that Sirt insufficiency may induce the calcification and atherosclerosis in cardiovascular tissues, through a mechanism involving upregulation of Runt-related transcription factor 2 (Runx2), which is the osteogenic transcriptional activator [16]. This suggests that Sirt may protect against the vascular calcification and maintain the vascular function with aging. To verify whether or not Sirt regulates chondrocyte activity in OA, we examined expressions of Sirt and Runx and production of MMP-13, and their correlations in human chondrocytes
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