Rheumatology Advance Access originally published online on September 25, 2007
Rheumatology 2007 46(12):1858-1859; doi:10.1093/rheumatology/kem254
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LETTERS TO THE EDITOR |
Cartilage oligomeric matrix protein in systemic sclerosis
1First Department of Internal Medicine, Sapporo Medical University School of Medicine, 2Sapporo Medical University, Japan
Correspondence to: Motohisa Yamamoto, First Department of Internal Medicine, Sapporo Medical University School of Medicine, South 1- West 16, Chuo-ku, Sapporo, Hokkaido, 0608543, Japan. E-mail: mocha{at}cocoa.plala.or.jp
SIR, Few biomarkers of systemic sclerosis (SSc) are useful, so physicians must largely depend on physical findings. However, we found that cartilage oligomeric matrix protein (COMP) appears clinically informative in patients with SSc. Here, we describe the relationship between COMP and SSc.
COMP is an extracellular glycoprotein belonging to the thrombospondin gene family that forms a disulfide-linked pentamer and is predominantly found in cartilage, tendons, ligaments and bone growth plates. COMP binds to type II collagen fibres and stabilizes the collagen fibre network [1, 2], and is carried to the bloodstream when cartilage is damaged in arthritis. COMP is thus considered a marker of some types of arthritis, such as osteoarthritis and rheumatoid arthritis [3, 4]. However a relationship has recently been identified between COMP and some types of fibrosis, such as chronic pancreatitis and renal fibrosis [5, 6]. We, therefore, measured the concentrations of serum COMP in SSc and analysed COMP expression in SSc and healthy skin specimens.
We analysed skin samples from 48 patients (6 men, 42 women; mean age 55.8 yrs; range 27–80 yrs) with SSc who attended Sapporo Medical University Hospital and 20 healthy volunteers (3 men, 17 women; mean age 53.9 yrs; range, 29–78 yrs). SSc patients fulfilled the classification of the American College of Rheumatology [7]. No SSc patients displayed any other rheumatic diseases. Radiography excluded arthritis as a cause of joint damage in the knees of patients. Clinical symptoms, complications and serological characteristics including autoantibodies were investigated. We initially measured serum levels of COMP in patients with and without arthralgia, interstitial pneumonia and auto-antibodies using enzyme-linked immunosorbent assay (ELISA). We then immunohistologically evaluated punch biopsies from SSc skin lesions and normal skin by anti-COMP antibody staining. We obtained written consent from all subjects according to the Declaration of Helsinki, and the local ethics committee reviewed the study and raised no objections.
SSc was diffuse cutaneous type in 19 patients and limited cutaneous type in 29 patients. Arthralgia due to SSc was seen in 19 patients, while interstitial pneumonia was present in 14 patients. Serological findings revealed anti-topoisomerase I antibodies in five patients, anti-centromere antibodies in 16 and anti-RNA polymerase III antibody and anti-Ku antibody in one patient each.
Serological analyses showed that serum COMP concentrations were higher in SSc patients than in healthy controls (Fig. 1). Mean serum COMP level was 13.5 U/ml (range, 0.0–33.4 U/ml), higher than the mean levels we previously identified in patients with rheumatoid arthritis (10.9 U/ml, n = 20) or Sjögren's syndrome (8.6 U/ml, n = 13) [4]. Mean serum levels of COMP were 16.8 U/ml in diffuse cutaneous SSc and 11.3 U/ml in limited cutaneous SSc (P < 0.005). Serum concentrations of COMP did not differ significantly between SSc patients with and without arthralgia (12.0 vs 14.5 U/ml, respectively; P = 0.18). Mean serum levels of COMP were also similar between groups with and without interstitial pneumonia (P = 0.85). Values also did not differ significantly with respect to the presence or absence of auto-antibodies. Immunohistological findings were surprising, with COMP expressed in coarse and hypertrophic dermis only from SSc patients.
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COMP was originally described in 1992 as a non-collagenous protein located mainly in cartilage [3], and has since been considered as a biomarker of joint disorders. However, COMP might in fact be involved in various pathogenic mechanisms, since the protein is up-regulated in degenerating acinar cells of chronic pancreatitis [5] and vascular lesions of atherosclerosis [8]. COMP might accumulate in abnormal sites associated with some types of fibrosis.
Human dermal fibroblasts can produce COMP in vitro [9]. A study by Tan et al. [10] using DNA-microarrays showed that the COMP gene is expressed more frequently in cultured dermal fibroblasts from SSc patients than in those from healthy controls. COMP protein also accumulates in SSc, but not in normal skin. We have further confirmed abnormal COMP protein expression in SSc skin samples by immunochemistry. COMP overexpression can stimulate excess matrix deposition.
The present study showed that serum COMP levels are significantly elevated in patients with SSc. This is the first report to describe a relationship between SSc and serum COMP, revealing that serum COMP levels are higher in diffuse cutaneous type than in limited cutaneous type. Serum COMP concentrations may reflect the degree of skin sclerosis. However, serum concentrations of COMP were not associated with SSc symptoms and complications, suggesting a derivation from abnormal sclerotic skin rather than from joints or organs. We are presently investigating correlations between serum COMP and skin thickness, and evaluating the feasibility of COMP as a novel biomarker of SSc.
Disclosure Statement: The authors have declared no conflicts of interest.
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[Abstract/Free Full Text] - Yamamoto M, Takahashi H, Ohara M, et al. [Evidence of cartilaginous benefit of treatment with infliximab in rheumatoid arthritis using measurement of serum COMP]. Nihon Rinsho Meneki Gakkai Kaishi (2007) 30:41–7.[Medline]
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[Abstract/Free Full Text] - Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum (1980) 23:581–90.[Web of Science][Medline]
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- Tan FK, Hildebrand BA, Lester MS, et al. Classification analysis of the transcriptosome of nonlesional cultured dermal fibroblasts from systemic sclerosis patients with early disease. Arthritis Rheum (2005) 52:865–76.[CrossRef][Medline]
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