Conditioned Media from Adipose-Tissue-Derived Mesenchymal Stem Cells Downregulate Degradative Mediators Induced by Interleukin-1β in Osteoarthritic Chondrocytes
Osteoarthritis (OA) is the most frequent joint disorder and an important cause of disability. Recent studies have shown the potential of adipose-tissue-derived mesenchymal stem cells (AD-MSC) for cartilage repair. We have investigated whether conditioned medium from AD-MSC (CM) may regulate in OA chondrocytes a number of key mediators involved in cartilage degeneration. CM enhanced type II collagen expression in OA chondrocytes while decreasing matrix metalloproteinase (MMP) activity in cell supernatants as well as the levels of MMP-3 and MMP-13 proteins and mRNA in OA chondrocytes stimulated with interleukin- (IL-) 1β. In addition, CM increased IL-10 levels and counteracted the stimulating effects of IL-1β on the production of tumor necrosis factor-α, IL-6, prostaglandin E2, and NO measured as nitrite and the mRNA expression of these cytokines, CCL-2, CCL-3, CCL-4, CCL-5, CCL-8, CCL-19, CCL-20, CXCL-1, CXCL-2, CXCL-3, CXCL-5, CXCL-8, cyclooxygenase-2, microsomal prostaglandin E synthase-1, and inducible NO synthase. These effects may be dependent on the inhibition of nuclear factor-κB activation by CM. Our data demonstrate the chondroprotective actions of CM and provide support for further studies of this approach in joint disease. 1. Introduction Osteoarthritis (OA) is a leading cause of disability in the elderly and has a significant impact on health care (reviewed in [1]). Although the pathogenesis of OA remains unclear, the chronic production of different mediators by articular tissues is believed to contribute to tissue degradation. Levels of proinflammatory cytokines such as interleukin- (IL-) 1 and tumor necrosis factor- (TNF ) are elevated in the inflamed synovium in OA, accompanied by the increased expression of their receptors and decreased levels of inhibitory proteins. These cytokines mediate cartilage destruction through the upregulation of inflammatory or catabolic genes and the downregulation of anti-inflammatory or anabolic genes in articular chondrocytes (reviewed in [2]). In particular, IL-1 reduces the expression of type II collagen [3] and increases the production of matrix metalloproteinases (MMPs) [4, 5], prostaglandin E2 (PGE2), cytokines, chemokines, reactive oxygen species, and nitric oxide (NO) [6, 7]. Chondrocytes are the main source of NO in OA articular tissues and the oxidative stress caused by this mediator has been related to degeneration in arthritic joints [8]. Therefore, NO can play a role in IL-1 -induced suppression of glycosaminoglycan and collagen synthesis, expression of MMPs, and activation of proenzymes [9].
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