Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Osteopontin in Systemic Sclerosis and Its Role in Dermal Fibrosis.
Wu2, Minghua, Schneider1, Daniel J., Mayes3, Maureen D., Assassi2, Shervin, Arnett4, Frank C., Tan5, Filemon K., Blackburn1, Michael R.
Department of Biochemistry and Molecular Biology, UTHSC-H, Houston, TX
Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, TX
University of Texas-Houston, Houston, TX
UT Medical School, Houston, TX
UT-Houston Med School, Houston, TX
Osteopontin (OPN) is a multifunctional cytokine produced during inflammation and tissue repair. OPN has been implicated in certain autoimmune diseases such as rheumatoid arthritis and as well as with fibrosis in disorders such as idiopathic pulmonary fibrosis and in mouse models of pulmonary fibrosis. Given the importance of autoimmunity and fibrosis in systemic sclerosis (SSc), we hypothesized that OPN is elevated in SSc patients and plays a critical role in the development of dermal fibrosis.
Plasma from a cohort of SSc patients (n= 319) and non-autoimmune disease controls (n= 144) were used to determine OPN levels by ELISA. Skin biopsies from SSc patients and healthy controls were used for immunohistological (IHC) analyses. To determine if OPN is a mediator of dermal fibrosis, OPN deficient (def) and wild type (WT) mice were compared in the bleomycin (bleo)-induced dermal fibrosis model.
Circulating levels of OPN were elevated in SSc patients (47.9±3.6 ng/ml) compared to healthy controls (28.3±3.8ng/ml, p=0.0009). OPN levels were elevated in both patients with limited and diffuse disease as well as anticentromere, anti-topoisomerase I and anti-RNA polymerase III positive SSc patients relative to controls. Compared to controls, SSc skin biopsies expressed OPN that localized to both fibroblast-like cells and macrophages on IHC analyses. Similarly, skin biopsies from mice treated with subcutaneous bleo had increased levels of OPN compared to PBS injected mice. Interestingly, using the bleo-induced dermal fibrosis model, OPN def. mice had markedly attenuated dermal fibrosis as quantitated by skin thickness (OPN def: 253±14 mm, WT 318±12 mm, p=0.001), collagen levels (OPN def: 263±35 mg/mg, WT 420±46 mg/mg, p=0.01) and myofibroblast accumulation in the lesional skin. Furthermore, OPN def. mice had decreased dermal inflammation, including decreased number of Mac-3 positive macrophages. Lastly, Col1a1, IL-6, PAI-1 and CTGF mRNA levels were significantly decreased in lesional skin of OPN def. compared to WT mice.
These data demonstrate that OPN is a mediator of dermal fibrosis, and suggest that OPN may be a potential biomarker and/or therapeutic target in SSc.
To cite this abstract, please use the following information:
Wu, Minghua, Schneider, Daniel J., Mayes, Maureen D., Assassi, Shervin, Arnett, Frank C., Tan, Filemon K., et al; Osteopontin in Systemic Sclerosis and Its Role in Dermal Fibrosis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :612