title: 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-1β 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-1β-induced MMP-13, tumor necrosis factor-α, 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-1β. Of importance is our finding that IL-6-stimulated MMP-13 expression was independent of IL-1β 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.
authors.affiliation: Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, Ohio.
authors.forename: Mohammad Shahidul
authors.initials: MS
authors.lastname: Makki
authors.affiliation: Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, Ohio. Electronic address: thaqqi@neomed.edu.
authors.forename: Tariq M
authors.initials: TM
authors.lastname: Haqqi
mesh_terms: D000368:Aged; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects; D024043:Collagen Type II / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007719:Knee Joint / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D010003:Osteoarthritis / Q000188:drug therapy*; D011509:Proteoglycans / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D024043:Collagen Type II; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053583:Interleukin-1beta; D011509:Proteoglycans; D014409:Tumor Necrosis Factor-alpha; D000077337:Vorinostat; D053509:Matrix Metalloproteinase 13