Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Steroid Receptor Coactivator-3 and Angiogenesis in Autoimmune Disease Associated Leg Ulcers.
Shanmugam1, Victoria K., Tassi2, Elena, Al-Otaiby2, Maram, Kallakury1, Bhaskar, Mete3, Mihriye, Attinger4, Christopher, Wellstein2, Anton
Delayed wound healing is a complication of several autoimmune diseases including scleroderma, rheumatoid arthritis and systemic lupus erythematosus (SLE). While the mechanisms of delayed healing in these patients are not known, we hypothesize that dysregulation of angiogenesis may play a role. Angiogenesis is critical in wound healing. Patients receiving bevacizumab and other vascular endothelial growth factor (VEGF) inhibitors exhibit impaired wound healing, and animal studies of angiogenesis in malignancy support this association.
The purpose of this study was to use immunohistochemistry (IHC) of formalin fixed paraffin embedded (FFPE) biopsy specimens from leg ulcers associated with autoimmune disease, diabetes and bevacizumab use to investigate the distribution of critical angiogenic markers. Steroid receptor coactivator-3 (SRC-3; also named Amplified in Breast Cancer-1) is a p160 steroid receptor coactivator that enhances NF-kB-mediated signaling in inflammatory disease, and modulates angiogenesis in malignancy. Fibroblast growth factor binding protein-1 (FGF-BP1) is another important molecule that is upregulated in wound healing, and acts as an angiogenic switch in malignancy.
FFPE samples were selected from the following groups: Diabetes Mellitus (n=3), Mixed Connective Tissue Disease (n=4), Systemic Lupus Erythematosus (n=5), Scleroderma (n=5) and bevacizumab use (n=2). The following stains were performed using standard IHC protocol: hematoxylin and eosin (H&E), steroid receptor coactivator-3 (SRC-3), fibroblast growth factor binding protein-1 (FGF-BP1), CD45, CD4, CD8, CD68 and CD34.
Blinded quantitative analysis at ×200 magnification using Image-J was used to quantify staining. Representative regions across each specimen were selected moving from intact to ulcerated tissue. Data was analyzed using Stata/IC 11.2 for Windows using linear regression and analysis of variance models to compare cell counts and ratio of blood vessel size between disease groups and across sampling fields.
Total CD34 staining as a measure of blood vessel density was similar across the disease groups. However, the ratio of large to small vessels was significantly lower for autoimmune ulcers and VEGF inhibitor-associated wounds compared to the diabetics (p=.005). Pairwise comparisons with Bonferroni adjustment showed that the mean ratio of large to small vessels was significantly greater for diabetics compared to the other group means.
Regression analysis estimating the differences in staining pattern adjusting for location of the sampling field found that steroid receptor coactivator-3 was significantly higher in the SLE group compared to other diseases (p< 0.001). We did not find associations with FGF-BP1.
In autoimmune wounds, the ratio of large to small blood vessels was significantly reduced suggesting dysregulation of blood vessel structure or maturation. SRC-3 was significantly higher in SLE-associated ulcers. This study provides preliminary data to support the hypothesis that dysregulation of anigiogenesis and in particular SRC-3 may play a critical role in wound healing in autoimmune disease.
To cite this abstract, please use the following information:
Shanmugam, Victoria K., Tassi, Elena, Al-Otaiby, Maram, Kallakury, Bhaskar, Mete, Mihriye, Attinger, Christopher, et al; Steroid Receptor Coactivator-3 and Angiogenesis in Autoimmune Disease Associated Leg Ulcers. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :27