title: IL-6 and soluble IL-6 receptor stimulate the production of MMPs and their inhibitors via JAK-STAT and ERK-MAPK signalling in human chondrocytes.
abstract: Elevated concentrations of IL-6 (interleukin-6) and sIL-6r (soluble IL-6 receptor) in the synovial fluid and serum of patients with arthritis have been implicated in joint cartilage destruction. This study examined the effects of IL-6 and sIL-6r on the expression of MMPs (matrix metalloproteinases), TIMPs (tissue inhibitor of metalloproteinases), the plasminogen activation system including tPA (tissue-type PA), uPA (urokinase-type PA) and PAI-1 (PA inhibitor type 1) using chondrocytes derived from normal human femur cartilage. The cells were cultured with or without 50 ng/ml IL-6 and/or 30 ng/ml sIL-6r in the presence or absence of the JAK3 (Janus kinase 3) inhibitor WHI-P131 or the MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular signal protein kinase) kinase] inhibitor PD98059 for up to 28 days. The expression of MMPs, TIMPs, uPA, tPA and PAI-1 was investigated at the mRNA and protein levels. MMP protein expression and pSTAT3 (phosphorylation of signal transducer and activator of transcription 3) and pERK (phosphorylation of ERK) were also measured. Treatment with both IL-6 and sIL-6r markedly increased the expression of MMP-1, MMP-13, TIMP-1 and PAI-1, while significantly decreasing the expression of tPA and uPA and stimulating pSTAT3 and pERK. Adding WHI-P131 or PD98059 decreased IL-6 and sIL-6r enhancement of MMP-1, -3 and -13. The results suggest that IL-6 and sIL-6r stimulate the production of MMPs and their inhibitor via JAK-STAT and ERK-MAPK signalling in chondrocytes.
authors.affiliation: Department of Fixed Prosthodontics and Division of Advenced Dental Treatment, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan. aida@dent.nihon-u.ac.jp
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Aida
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Honda
authors.forename: Shihoko
authors.initials: S
authors.lastname: Tanigawa
authors.forename: Go
authors.initials: G
authors.lastname: Nakayama
authors.forename: Hideo
authors.initials: H
authors.lastname: Matsumura
authors.forename: Naoto
authors.initials: N
authors.lastname: Suzuki
authors.forename: Osamu
authors.initials: O
authors.lastname: Shimizu
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeichi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Makimura
authors.forename: Masao
authors.initials: M
authors.lastname: Maeno
mesh_terms: D002356:Cartilage / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D012995:Solubility; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D005419:Flavonoids; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019947:Receptors, Interleukin-6; C051321:SERPINE1 protein, human; D019714:Tissue Inhibitor of Metalloproteinases; C116180:WHI P131; D053616:Janus Kinase 3; D020928:Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one