title: Celastrol, an inhibitor of heat shock protein 90β potently suppresses the expression of matrix metalloproteinases, inducible nitric oxide synthase and cyclooxygenase-2 in primary human osteoarthritic chondrocytes.
abstract: Overexpression of matrix metalloproteinases (MMPs), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have long been suggested to play crucial roles in the progression of osteoarthritis. Studies have showed that selective MMPs, iNOS and COX-2 inhibitors possess great potential as chondroprotective agents for osteoarthritis. Therefore, there have been intensive efforts to develop novel natural compounds that target MMPs, iNOS and COX-2 activation. As interleukin-1β (IL-1β) is one of the key proinflammatory cytokines contributing to the progression in osteoarthritis, we investigated the effect of celastrol, a triterpenoid compound extracted from the Chinese herb Tript erygium wilfordii Hook F, in neutralizing the inflammatory effects of IL-1β on MMPs, iNOS and COX-2 expression as well as nitric oxide (NO) and prostaglandin E2 (PGE2) production. Protein expression was detected by Western blotting or by enzyme-linked immunosorbent assay (ELISA); messenger RNA (mRNA) expression was examined by real-time reverse transcription-polymerase chain reaction analysis and the involvement of signal pathway was assessed by transient transfection and luciferase activity assay. We found that treatment of primary human osteoarthritic chondrocytes with various concentrations of celastrol resulted in striking decrease in the expression of MMP-1, MMP-3, MMP-13, iNOS-2 and COX-2. In addition, celastrol treatment of cells also inhibited the activation of nuclear factor-kappa B (NF-kappaB). Taken together, we provide evidence that celastrol can protect human chondrocytes by downregulating the expression of MMPs, iNOS and COX-2. We suggest that celastrol could be a useful agent for prevention and treatment of osteoarthritis.
authors: Department of Orthopedic Surgery, The Second Affiliated Hospital of School of Medicine, Zhejiang University, Jie Fang Road 88#, 310009 Hangzhou, People's Republic of China.
authors: Qian-Hai
authors: QH
authors: Ding
authors: Ye
authors: Y
authors: Cheng
authors: Wei-Ping
authors: WP
authors: Chen
authors: Hui-Ming
authors: HM
authors: Zhong
authors: Xiang-Hua
authors: XH
authors: Wang
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D010003:Osteoarthritis / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D053583:Interleukin-1beta; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020782:Matrix Metalloproteinases; D015232:Dinoprostone; C050414:celastrol