title: Novel p38 mitogen-activated protein kinase inhibitor R-130823 protects cartilage by down-regulating matrix metalloproteinase-1,-13 and prostaglandin E2 production in human chondrocytes.
abstract: In order to study the involvement of mitogen-activated protein kinase p38 in osteoarthritis, we investigated the effect of novel p38 inhibitor R-130823 {2-(4-fluorophenyl)-4-(1-phenethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole} on human chondrocytes and bovine cartilage. In human primary chondrocytes, the production of matrix metalloproteinase-13 and -1 (MMP-13 and -1) and prostaglandin E2 (PGE2) was induced by interleukin-1beta. Pretreatment with R-130823 inhibited the release of MMP-13, MMP-1 and PGE2 with IC50 values of 20, 230 and 3.9 nM, respectively. The inhibitory activity was also confirmed by a decrease in MMP-13 release from human chondrosarcoma cell line SW1353 with an IC50 value of 17 nM. Ribonuclease protection assay on human primary chondrocytes indicated that MMP-13 and MMP-1 mRNA levels almost reached the maximum 14 h after IL-1 stimulation, while cyclooxygenase-2 (COX-2) mRNA quickly reached the maximum 4 h after the stimulation. R-130823 down-regulated the steady-state levels of MMP-13 and MMP-1 mRNA with IC50 values of 4.2 and 79 nM, respectively. The COX-2 mRNA level was also suppressed with an IC50 value of 21 nM. In the explant culture of bovine nasal cartilage, R-130823 suppressed the collagen cleavage induced by interleukin-1alpha and oncostatin M, but not IL-1beta-mediated glycosaminoglycan release. These results suggest that activated p38 accelerates cartilage breakdown by enhancing the expression of MMPs responsible for collagen cleavage, which thus implies chondroprotective effects of p38 inhibitors in osteoarthritis.
authors.affiliation: Biological Research Laboratories, Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. yhwada@sankyo.co.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Kohei
authors.initials: K
authors.lastname: Shimada
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Tomio
authors.initials: T
authors.lastname: Kimura
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ushiyama
mesh_terms: D000465:Algorithms; D000818:Animals; D015153:Blotting, Western; D002356:Cartilage / Q000187:drug effects* / Q000201:enzymology; D002417:Cattle; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000096:biosynthesis*; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone / Q000096:biosynthesis*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D009666:Nose; D023282:Nuclease Protection Assays; D011725:Pyridines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D012333:RNA, Messenger; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone; C497778:2-(4-fluorophenyl)-4-(1-phenethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole