title: Response of chondrocytes to shear stress: antagonistic effects of the binding partners Toll-like receptor 4 and caveolin-1.
abstract: Osteoarthritis (OA) is often a consequence of excessive mechanical loading of cartilage, which produces hydrostatic stress, tensile strain, and fluid flow. Application of high fluid shear to chondrocytes recapitulates the earmarks of OA, as evidenced by the induction of cyclooxygenase-2, prostaglandins (PGs), and interleukin-6 (IL-6). Here, we delineated the signaling pathway by which high fluid shear mediates the temporal regulation of IL-6 synthesis in human chondrocytes. We determined that Toll-like receptor 4 (TLR4) and caveolin-1 are binding partners in chondrocytes. Their expression is temporally regulated by fluid shear via the sequential up-regulation of microsomal PGE synthase-1 (mPGES-1) and L-PGDS. High shear stress rapidly induces an 8-fold up-regulation of TLR4 expression via an mPGES-1-dependent pathway, whereas prolonged shear exposure concurrently down-regulates TLR4 by >4-fold and up-regulates caveolin-1 expression by > 2.5-fold in an L-PGDS-dependent manner. TLR4 and caveolin-1 exert opposing effects on the activation of ERK1/2, PI3-K and PKA signaling pathways, which, in turn, regulate the NF-κB-dependent IL-6 synthesis in a time-dependent fashion. Reconstructing the signaling network regulating shear-induced IL-6 expression in chondrocytes may provide insights for developing therapeutic strategies to combat osteoarthritis.
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA.
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Zhu
authors.forename: Ziqiu
authors.initials: Z
authors.lastname: Tong
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Konstantopoulos
mesh_terms: D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D019902:Chondrocytes / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015230:Prostaglandin D2 / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D033081:Shear Strength; D013312:Stress, Physiological; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; D015230:Prostaglandin D2