title: Mapping the CRF-urocortins system in human osteoarthritic and rheumatoid synovial fibroblasts: effect of vasoactive intestinal peptide.
abstract: In addition to the brain and pituitary gland, the corticotrophin-releasing factor (CRF) system is expressed in peripheral tissues. In this study we characterize the expression of CRF, urocortins (UCN1, UCN2, and UCN3), and their receptors (CRFR1 and CRFR2) in osteoarthritis (OA) and rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). Moreover, we analyze the vasoactive intestinal peptide (VIP) effect on the CRF system, as well as its physiological consequences on mediators of inflammatory/destructive processes. CRF and UCNs exhibit differential pattern in OA and RA-FLS. By real-time PCR we detected more expression of CRF and UCN1 in RA, and UCN2 and UCN3 in OA, while the CRFR2 expression was similar. In RA-FLS VIP treatment resulted in a significant decrease of the proinflammatory peptides, CRF and UCN1, and a significant increase of the potential anti-inflammatory agents, UCN3 and CRFR2. Using Western blot assays, we showed that the ratio between phospho-CREB (p-CREB) and c-AMP response element-binding (CREB) is higher in OA and significantly lower in RA-FLS after VIP treatment, with consequences upon cAMP response element in CRF and UCN1 genes. Real-time PCR and EIA proved that VIP significantly inhibits cycloxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in RA-FLS. In all cases, we consider significant data when P < 0.05. These data indicate a role of endogenous CRF, UCNs, and CRFR2 in the OA and RA joint microenvironment. We confirm the anti-inflammatory function of VIP, through the modulation of the expression of CRF system that impacts in a reduction of mediators with inflammatory/destructive functions, supporting its therapeutic potential in rheumatic diseases.
authors.affiliation: Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Selene
authors.initials: S
authors.lastname: Pérez-García
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Juarranz
authors.forename: Mar
authors.initials: M
authors.lastname: Carrión
authors.forename: Irene
authors.initials: I
authors.lastname: Gutiérrez-Cañas
authors.forename: Andrew
authors.initials: A
authors.lastname: Margioris
authors.forename: José L
authors.initials: JL
authors.lastname: Pablos
authors.forename: Christos
authors.initials: C
authors.lastname: Tsatsanis
authors.forename: Rosa P
authors.initials: RP
authors.lastname: Gomariz
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D015153:Blotting, Western; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D054832:Urocortins / Q000235:genetics / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
chemical_list: D000893:Anti-Inflammatory Agents; C115163:CREB1 protein, human; C101531:CRF receptor type 2; D017362:Cyclic AMP Response Element-Binding Protein; D052246:Cyclooxygenase 2 Inhibitors; D018836:Inflammation Mediators; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; C426705:UCN2 protein, human; C426704:UCN3 protein, human; D054832:Urocortins; D014660:Vasoactive Intestinal Peptide; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone