title: WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production.
abstract: WNT5A has recently been implicated in inflammatory processes, but its role as a bone marrow stromal cell (BMSC)-derived mediator of joint inflammation in arthritis is unclear. Here, we investigated whether inflammatory stimuli induce WNT5A in BMSC to control inflammatory responses. WNT5A levels were determined in human BMSC after stimulation with lipopolysaccharide (LPS) or tumor necrosis factor α (TNF-α,) and in synovial cells and tissue of patients with rheumatoid arthritis (RA) and human TNF-α transgenic (hTNFtg) mice. A microarray analysis of WNT5A-treated murine osteoblasts was performed using Affymetrix gene chips. The regulation of cytokine/chemokine expression was confirmed by qPCR, ELISA, and Luminex technology in BMSC after stimulation with WNT5A or WNT5A knockdown. Relevant signaling pathways were identified using specific inhibitors. Migration of MACS-purified T lymphocytes and monocytes was assessed using the FluoroBlok system. WNT5A expression was increased threefold in BMSC after stimulation with LPS or TNF-α. Synovial fibroblasts from patients with RA showed a twofold increase of WNT5A expression compared with control cells, and its expression was highly induced in the synovial tissue of patients with RA and hTNFtg mice. Microarray analysis of WNT5A-treated osteoblasts identified cytokines and chemokines as targets. The induction of IL-1β, IL-6, CCL2, CCL5, CXCL1, and CXCL5 by WNT5A was confirmed in BMSC and depended on the activation of the NF-κB, mitogen-activated protein (MAPK), and Akt pathways. Accordingly, knockdown of WNT5A markedly reduced the basal and LPS-induced cytokine/chemokine production. Finally, migration of monocytes and T cells toward the supernatant of WNT5A-treated BMSC was increased by 25% and 20%, respectively. This study underlines the critical role of BMSC-derived WNT5A in the regulation of inflammatory processes and suggests its participation in the pathogenesis of RA.
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University, Dresden, Germany. martina.rauner@uniklinikum-dresden.de
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.forename: Nicola
authors.initials: N
authors.lastname: Stein
authors.forename: Maria
authors.initials: M
authors.lastname: Winzer
authors.forename: Claudia
authors.initials: C
authors.lastname: Goettsch
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.forename: Joachim
authors.initials: J
authors.lastname: Albers
authors.forename: Jochen
authors.initials: J
authors.lastname: Schulze
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
mesh_terms: D000328:Adult; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement; D002469:Cell Separation; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051153:Wnt Proteins / Q000096:biosynthesis*; D000071818:Wnt-5a Protein
chemical_list: D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein