title: CTGF induces monocyte chemoattractant protein-1 expression to enhance monocyte migration in human synovial fibroblasts.
abstract: Connective tissue growth factor (CTGF; also known as CCN2) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. CTGF is abundantly expressed in osteoarthritis (OA). Migration and infiltration of mononuclear cells to inflammatory sites are playing important roles during OA pathogenesis. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is the key chemokine that regulates migration and infiltration of monocytes. However, the effect of CTGF on MCP-1 expression and monocyte migration is largely unknown. Our results showed that MCP-1 was highly expressed in OA synovial fibroblasts (OASFs) as compared with normal SFs. Directly applying OASFs with CTGF increased MCP-1 expression in a concentration- and a time-dependent manner. CTGF mediated MCP-1 production was attenuated by αvβ5 integrin neutralized antibody. Pretreatment with focal adhesion kinase (FAK), MEK, AP-1, and NF-κB inhibitors also inhibited the potentiating action of CTGF. CTGF-mediated increase of NF-κB and AP-1 luciferase activity was inhibited by FAK, MEK, and ERK inhibitors or mutants. In vitro chemotaxis assay showed that OA synovial fluid and supernatants from CTGF treated OASFs increased migration of monocyte. In addition, CTGF-mediated migration was inhibited by the FAK and MEK inhibitors. Taken together, our results indicated that CTGF enhances the migration of monocyte cells by increasing MCP-1 expression through the αvβ5 integrin, FAK, MEK, ERK, and NF-κB/AP-1 signal transduction pathway.
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Shan-Chi
authors.initials: SC
authors.lastname: Liu
authors.forename: Chin-Jung
authors.initials: CJ
authors.lastname: Hsu
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Fong
authors.forename: Show-Mei
authors.initials: SM
authors.lastname: Chuang
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism; D015398:Signal Transduction; D013582:Synovial Fluid / Q000378:metabolism
chemical_list: C526317:CCN2 protein, human; D018932:Chemokine CCL2; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D055513:Connective Tissue Growth Factor; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048728:MAP Kinase Kinase Kinase 1