title: Hyaluronan inhibits TLR-4 dependent cathepsin K and matrix metalloproteinase 1 expression in human fibroblasts.
abstract: Rheumatoid synovial fibroblasts (RSF) are activated by toll-like receptor (TLR) signaling pathways during the pathogenesis of rheumatoid arthritis (RA). Cathepsin K is highly expressed by RSF, and is known to play a key role in the degradation of type I and type II collagen. Cathepsin K is considered to be implicated in the degradation of bone and cartilage in RA. Recent observations have shown that hyaluronan (HA) is an important inhibitor of inflammation. In the present study, we show that lipopolysaccharide (LPS) stimulation significantly increases cathepsin K expression by real-time PCR and western blotting analysis via a TLR-4 signaling pathway. Furthermore, we demonstrate that HA suppresses LPS-induced cathepsin K expression, which is dependent on CD44 but not intercellular adhesion molecule-1 (ICAM-1) interaction. We also show that HA suppresses LPS-induced matrix metalloproteinase-1 (MMP-1) expression, which is dependent on both CD44 and ICAM-1 interaction. We conclude that the anti-inflammatory effect of HA occurs through crosstalk between more than one HA receptor. Our study provides evidence for HA mediated suppression of LPS-induced cathepsin K and MMP-1 expression, supporting a protective effect of HA in RA.
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hirabara
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kojima
authors.forename: Nobunori
authors.initials: N
authors.lastname: Takahashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hanabayashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D008070:Lipopolysaccharides; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000096:biosynthesis*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid; C534130:CTSK protein, human; D056657:Cathepsin K; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1