Abstract: Increased Circulating Concentrations of the Counteradhesive Proteins SPARC and Thrombospondin-1 in Systemic Sclerosis (Scleroderma). Relationship to Platelet and Endothelial Cell Activation

Increased Circulating Concentrations of the Counteradhesive Proteins SPARC and Thrombospondin-1 in Systemic Sclerosis (Scleroderma). Relationship to Platelet and Endothelial Cell Activation

RICHARD F. MACKO, ALLAN C. GELBER, BRADFORD A. YOUNG, MARK H. LOWITT, BARBARA WHITE, FREDRICK M. WIGLEY, and SIMEON E. GOLDBLUM

ABSTRACT.

Objective. To determine whether circulating concentrations of the counteradhesive proteins SPARC (secreted protein acidic and rich in cysteine) and thrombospondin-1 (TSP-1) are elevated in scleroderma (systemic sclerosis, SSc). The relationship of these counteradhesive proteins to measures of platelet and endothelial cell activation was examined.

Methods. Plasma from 45 patients with SSc (26 limited form, 19 diffuse) and 22 age and sex matched controls was assayed for SPARC, TSP-1, ß-thromboglobulin (ßTG), and platelet factor 4 (PF4), 2 distinct platelet a-granule products, and soluble E-selectin, a marker of endothelial cell activation.

Results. The mean (± SE) SPARC concentration was greater in patients with limited SSc (124.0 ± 9.6 ng/ml) compared to controls (66.8 ± 8.0 ng/ml) (p = 0.0005), whereas in patients with diffuse SSc (74.1 ± 7.9 ng/ml) it was not. Elevated SPARC concentrations in the limited SSc group could not be ascribed to either platelet or endothelial cell activation. TSP-1 concentrations were also increased in SSc patients (n = 29) compared to controls (n = 11) (2.98 ± 0.12 vs 2.4 ± 0.21 log transformed ng/ml; p < 0.02). Unlike SPARC, TSP-1 concentrations correlated with both ßTG (r = 0.57, p = 0.0014) and PF4 (r = 0.41, p = 0.026) levels, indicating that increased TSP-1 could, in part, be explained through elevated platelet a-granule release in SSc patients. Plasma levels of ßTG, PF4, and E-selectin were each similarly elevated (p < 0.003) in patients with both limited and diffuse SSc compared to controls.

Conclusion. That circulating SPARC and TSP-1 are elevated in patients with SSc raises the possibility that counteradhesive proteins, which regulate vascular organization and remodeling, might contribute to the pathogenesis of SSc vasculopathy. (J Rheumatol 2002;29:2565-70)

Key Indexing Terms:

SYSTEMIC SCLEROSIS
SPARC
THROMBOSPONDIN-1
PLATELET FACTOR 4
ß-THROMBOGLOBULIN
E-SELECTIN

From the Departments of Neurology, Medicine, and Dermatology, VA Maryland Health Care Center, University of Maryland at Baltimore; and the Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

Supported in part by the Office of Research and Development, Department of Veterans Affairs (SEG); the Scleroderma Research Foundation, Santa Barbara, CA (BW, FMW, SEG); grant RO1 HL63217 from the NIH (SEG); and an Arthritis Foundation Arthritis Investigator Award (ACG).

R.F. Macko, MD, Department of Neurology, VA Maryland Health Care Center; A.C. Gelber, MD, MPH, PhD, Departments of Medicine and Epidemiology, Johns Hopkins University; B.A. Young, PhD; B. White, MD; S.E. Goldblum, MD, Department of Medicine; M.H. Lowitt, MD, Department of Dermatology, VA Maryland Health Care Center; F.M. Wigley, MD, Department of Medicine, Johns Hopkins University.

Dr. Wigley and Dr. Goldblum contributed equally to this report.

Address reprint requests to Dr. S.E. Goldblum, Medical Service (111), 5D-139, VA Maryland Health Care System, 10 North Greene Street, Baltimore, MD 21201. E-mail: simeon.goldblum@med.va.gov

Submitted October 24, 2001; revision accepted June 14, 2002.