Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

Abstract

Osteoarthritis (OA) is the most common whole-joint disease and is characterized by progressive loss of the cartilage matrix. Matrix metallopeptidase-13 (MMP-13) is a highly active and an abundantly expressed protease in OA cartilage and chondrocytes and degrades type II collagen and proteoglycans. We investigated the mechanism of MMP-13 suppression by histone deacetylase inhibitor vorinostat (SAHA). OA chondrocytes were obtained from knee cartilage after enzymatic digestion and treated with IL-1b in the absence or presence of various histone deacetylase inhibitors. Gene expression was quantified using quantitative RT-PCR. Protein expression and chromatin modifications were determined by Western immunoblotting using specific antibodies. The effect of IL-6 on the expression of MMP-13 was determined by treating chondrocytes with recombinant IL-6 or by IL6 knockdown using IL6-specific siRNA. We found that SAHA is a potent suppressor of IL-1beinduced MMP-13, tumor necrosis factor-a, and other catabolic marker expression in OA chondrocytes. Interestingly, SAHA rescued the COL2A1 and ACAN expression in OA chondrocytes that was down-regulated by IL-1b. Of importance is our finding that IL-6estimulated MMP-13 expression was independent of IL-1b stimulation and was blocked by SAHA, suggesting that SAHA inhibits IL-6 signaling in OA chondrocytes. Taken together, our results suggest that SAHA could be used as a therapeutic agent for the management of OA. (Am J Pathol 2016 http:// dx

Hydrostatic Pressure Regulates MicroRNA Expression Levels in Osteoarthritic Chondrocyte Cultures via the Wnt/β-Catenin Pathway

“…Interestingly, the expression levels of this protein were higher in OA cartilage than in normal tissue [ 42 ], as also confirmed by our data. Furthermore, the inhibition of HDAC-4 by Vorinostat (SAHA) significantly reduced IL-1β/IL-6-induced expression of catabolic genes, especially MMP-13 , in human OA cartilage explants and chondrocytes [ 43 ]. Following in vitro transfection studies, HDAC-4 was identified as a direct target gene of miR-365 [ 23 ].…”

Lixisenatide attenuates advanced glycation end products (AGEs)-induced degradation of extracellular matrix in human primary chondrocytes

“…As a class of proinflammatory cytokines, interleukins (ILs) have been shown to play critical roles in a wide range of chronic inflammatory diseases including OA. Of these, the expression of IL-6, which is upregulated by oxidative stress and ROS, has been shown to be involved in the pathogenesis of OA [14,28]. Furthermore, this response is mediated through activation of the NF-jB signaling pathway [29,30].…”

Histone Deacetylase Inhibitory Approaches for the Management of Osteoarthritis

“…Vorinostat was first approved in 2006 by the US Food and Drug Administration for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma in whom other treatments have failed. The study by Makki and Haqqi, 2 showing vorinostat-mediated suppression of MMP-13 through inhibition of IL-6 in chondrocytes, suggests the potential of vorinostat as a therapeutic agent for the management of OA.…”

“…As the first report suggesting HDAC inhibitor vorinostat as a suppressor of IL-6einduced signaling events in OA, this study has a potential of opening new avenues in OA management. 2 Indeed, hyperacetylation of histone proteins up-regulates cell cycle inhibitors (p21 Cip1 , p27 Kip1 , p16 INK4 ), represses inflammatory cytokines (IL-1, IL-8, tumor necrosis factor-a, TGF-b), and down-regulates immune stimulators (IL-6, IL-10, CD154). 13 Furthermore, aberrant HDAC activity has been linked to a wide variety of pathological conditions.…”

“…In this issue of The American Journal of Pathology, Makki and Haqqi 2 have found that the drug vorinostat, which is a class I and II HDAC inhibitor, blocks IL-1beinduced expression of matrix metallopeptidase (MMP)-13, tumor necrosis factor-a, and other catabolic factors in human osteoarthritis (OA) chondrocytes obtained from the human knee cartilage. 2 Moreover, vorinostat was also found to rescue the collagen type II a and aggrecan proteoglycan expression in OA chondrocytes, which were down-regulated by IL-1b. In addition, the authors have demonstrated that IL6estimulated MMP-13 expression was independent of IL-1b stimulation and was blocked by vorinostat, suggesting that vorinostat inhibits IL-6 signaling in chondrocytes.…”