title: Osteopontin in systemic sclerosis and its role in dermal fibrosis.
abstract: Osteopontin (OPN) is a matricellular protein with proinflammatory and profibrotic properties. Previous reports demonstrate a role for OPN in wound healing and pulmonary fibrosis. Here, we determined whether OPN levels are increased in a large cohort of patients with systemic sclerosis (SSc) and whether OPN contributes to the development of dermal fibrosis. The plasma OPN levels were increased in SSc patients, including patients with limited and diffuse disease, compared with healthy controls. Immunohistology demonstrated OPN on fibroblast-like and inflammatory cells in SSc skin and lesional skin from mice in the bleomycin (bleo)-induced dermal fibrosis model. OPN-deficient (OPN(-/-)) mice developed less dermal fibrosis compared with wild-type (WT) mice in the bleo-induced dermal fibrosis model. Additional in vivo studies have demonstrated that lesional skin from OPN(-/-)mice had fewer Mac-3-positive cells, fewer myofibroblasts, decreased transforming growth factor (TGF)-β and genes in the TGF-β pathway, and decreased numbers of cells expressing phosphorylated SMAD2 (pSMAD) and extracellular signal-regulated kinase. In vitro, OPN(-/-) dermal fibroblasts had decreased migratory capacity but similar phosphorylation of SMAD2 by TGF-β. Finally, TGF-β production by OPN-deficient macrophages was reduced compared with WT. These data demonstrate an important role for OPN in the development of dermal fibrosis and suggest that it may be a new therapeutic target in SSc.
authors.affiliation: Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Minghua
authors.initials: M
authors.lastname: Wu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schneider
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: Filemon K
authors.initials: FK
authors.lastname: Tan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Agarwal
mesh_terms: D000328:Adult; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005355:Fibrosis / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C506896:Spp1 protein, mouse; D016212:Transforming Growth Factor beta; D053495:Osteopontin; D001761:Bleomycin