Skip to main content
Top
Published in: Arthritis Research & Therapy 6/2013

Open Access 01-12-2013 | Research article

Cartilage oligomeric matrix protein-induced complement activation in systemic sclerosis

Authors: Kaisa E Otteby, Emelie Holmquist, Tore Saxne, Dick Heinegård, Roger Hesselstrand, Anna M Blom

Published in: Arthritis Research & Therapy | Issue 6/2013

Login to get access

Abstract

Introduction

Complexes between cartilage oligomeric matrix protein (COMP) and the complement activation product C3b have been found in the circulation of patients with rheumatoid arthritis and systemic lupus erythematosus. In systemic sclerosis (SSc) COMP expression in the skin is upregulated both in lesional and non-lesional skin, which is also reflected in an increased amount of circulating COMP. We investigated the presence of COMP-C3b complexes in serum and skin biopsies of patients with SSc.

Methods

The presence of COMP and COMP-C3b complexes in the serum of 80 patients with limited cutaneous SSc (lcSSc, n = 40) and diffuse cutaneous SSc (dcSSc, n = 40) and 97 healthy controls was measured by ELISA and correlated to different clinical parameters. Samples were collected both at baseline and after three to five years to assess longitudinal changes in COMP-C3b complex levels. Furthermore, skin biopsies from seven patients with dcSSc and three healthy controls were analyzed for expression of COMP and deposition of C3b and IgG.

Results

Serum levels of COMP-C3b were found to be elevated in both dcSSc and lcSSc compared to healthy controls and decreased at the second measurement in patients on immunosuppressive therapy. No co-localization of COMP and C3b was found in the skin biopsies, indicating that the COMP-C3b complexes are formed upon release of COMP into the circulation.

Conclusion

COMP-C3b complexes are found in the serum of patients with SSc. The lack of co-localization between COMP and C3b in the skin suggests that COMP does not drive complement activation in the skin in SSc.
Appendix
Available only for authorised users
Literature
1.
go back to reference Sticherling M: Systemic sclerosis - dermatological aspects. Part 1: pathogenesis, epidemiology, clinical findings. J Dtsch Dermatol Ges. 2012, 10: 705-718.PubMed Sticherling M: Systemic sclerosis - dermatological aspects. Part 1: pathogenesis, epidemiology, clinical findings. J Dtsch Dermatol Ges. 2012, 10: 705-718.PubMed
2.
go back to reference Fleischmajer R, Gay S, Meigel WN, Perlish JS: Collagen in the cellular and fibrotic stages of scleroderma. Arthritis Rheum. 1978, 21: 418-428. 10.1002/art.1780210404.CrossRefPubMed Fleischmajer R, Gay S, Meigel WN, Perlish JS: Collagen in the cellular and fibrotic stages of scleroderma. Arthritis Rheum. 1978, 21: 418-428. 10.1002/art.1780210404.CrossRefPubMed
3.
go back to reference Martin P, Teodoro WR, Velosa AP, de Morais J, Carrasco S, Christmann RB, Goldenstein-Schainberg C, Parra ER, Katayama ML, Sotto MN, Capelozzi VL, Yoshinari NH: Abnormal collagen V deposition in dermis correlates with skin thickening and disease activity in systemic sclerosis. Autoimmun Rev. 2012, 11: 827-835. 10.1016/j.autrev.2012.02.017.CrossRefPubMed Martin P, Teodoro WR, Velosa AP, de Morais J, Carrasco S, Christmann RB, Goldenstein-Schainberg C, Parra ER, Katayama ML, Sotto MN, Capelozzi VL, Yoshinari NH: Abnormal collagen V deposition in dermis correlates with skin thickening and disease activity in systemic sclerosis. Autoimmun Rev. 2012, 11: 827-835. 10.1016/j.autrev.2012.02.017.CrossRefPubMed
4.
go back to reference Farina G, Lemaire R, Korn JH, Widom RL: Cartilage oligomeric matrix protein is overexpressed by scleroderma dermal fibroblasts. Matrix Biol. 2006, 25: 213-222. 10.1016/j.matbio.2006.01.007.CrossRefPubMed Farina G, Lemaire R, Korn JH, Widom RL: Cartilage oligomeric matrix protein is overexpressed by scleroderma dermal fibroblasts. Matrix Biol. 2006, 25: 213-222. 10.1016/j.matbio.2006.01.007.CrossRefPubMed
5.
go back to reference Yamamoto M, Takahashi H, Suzuki C, Naishiro Y, Yamamoto H, Imai K, Shinomura Y: Cartilage oligomeric matrix protein in systemic sclerosis. Rheumatology. 2007, 46: 1858-1859. 10.1093/rheumatology/kem254.CrossRefPubMed Yamamoto M, Takahashi H, Suzuki C, Naishiro Y, Yamamoto H, Imai K, Shinomura Y: Cartilage oligomeric matrix protein in systemic sclerosis. Rheumatology. 2007, 46: 1858-1859. 10.1093/rheumatology/kem254.CrossRefPubMed
6.
go back to reference Farina G, Lemaire R, Pancari P, Bayle J, Widom RL, Lafyatis R: Cartilage oligomeric matrix protein expression in systemic sclerosis reveals heterogeneity of dermal fibroblast responses to transforming growth factor beta. Ann Rheum Dis. 2009, 68: 435-441. 10.1136/ard.2007.086850.CrossRefPubMed Farina G, Lemaire R, Pancari P, Bayle J, Widom RL, Lafyatis R: Cartilage oligomeric matrix protein expression in systemic sclerosis reveals heterogeneity of dermal fibroblast responses to transforming growth factor beta. Ann Rheum Dis. 2009, 68: 435-441. 10.1136/ard.2007.086850.CrossRefPubMed
7.
go back to reference Tan FK, Hildebrand BA, Lester MS, Stivers DN, Pounds S, Zhou X, Wallis DD, Milewicz DM, Reveille JD, Mayes MD, Jin L, Arnett FC: Classification analysis of the transcriptosome of nonlesional cultured dermal fibroblasts from systemic sclerosis patients with early disease. Arthritis Rheum. 2005, 52: 865-876. 10.1002/art.20871.CrossRefPubMed Tan FK, Hildebrand BA, Lester MS, Stivers DN, Pounds S, Zhou X, Wallis DD, Milewicz DM, Reveille JD, Mayes MD, Jin L, Arnett FC: Classification analysis of the transcriptosome of nonlesional cultured dermal fibroblasts from systemic sclerosis patients with early disease. Arthritis Rheum. 2005, 52: 865-876. 10.1002/art.20871.CrossRefPubMed
8.
go back to reference Agarwal P, Zwolanek D, Keene DR, Schulz JN, Blumbach K, Heinegård D, Zaucke F, Paulsson M, Krieg T, Koch M, Eckes B: Collagen XII and XIV, new partners of cartilage oligomeric matrix protein in the skin extracellular matrix suprastructure. J Biol Chem. 2012, 287: 22549-22559. 10.1074/jbc.M111.335935.PubMedCentralCrossRefPubMed Agarwal P, Zwolanek D, Keene DR, Schulz JN, Blumbach K, Heinegård D, Zaucke F, Paulsson M, Krieg T, Koch M, Eckes B: Collagen XII and XIV, new partners of cartilage oligomeric matrix protein in the skin extracellular matrix suprastructure. J Biol Chem. 2012, 287: 22549-22559. 10.1074/jbc.M111.335935.PubMedCentralCrossRefPubMed
9.
go back to reference Rosenberg K, Olsson H, Mörgelin M, Heinegård D: Cartilage oligomeric matrix protein shows high affinity zinc-dependent interaction with triple helical collagen. J Biol Chem. 1998, 273: 20397-20403. 10.1074/jbc.273.32.20397.CrossRefPubMed Rosenberg K, Olsson H, Mörgelin M, Heinegård D: Cartilage oligomeric matrix protein shows high affinity zinc-dependent interaction with triple helical collagen. J Biol Chem. 1998, 273: 20397-20403. 10.1074/jbc.273.32.20397.CrossRefPubMed
10.
go back to reference Halasz K, Kassner A, Mörgelin M, Heinegård D: COMP acts as a catalyst in collagen fibrillogenesis. J Biol Chem. 2007, 282: 31166-31173. 10.1074/jbc.M705735200.CrossRefPubMed Halasz K, Kassner A, Mörgelin M, Heinegård D: COMP acts as a catalyst in collagen fibrillogenesis. J Biol Chem. 2007, 282: 31166-31173. 10.1074/jbc.M705735200.CrossRefPubMed
11.
go back to reference Hedbom E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, Rosa-Pimentel E, Sommarin Y, Wendel M, Oldberg A, Heinegård D: Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage. J Biol Chem. 1992, 267: 6132-6136.PubMed Hedbom E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, Rosa-Pimentel E, Sommarin Y, Wendel M, Oldberg A, Heinegård D: Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage. J Biol Chem. 1992, 267: 6132-6136.PubMed
12.
go back to reference DiCesare P, Hauser N, Lehman D, Pasumarti S, Paulsson M: Cartilage oligomeric matrix protein (COMP) is an abundant component of tendon. FEBS Lett. 1994, 354: 237-240. 10.1016/0014-5793(94)01134-6.CrossRefPubMed DiCesare P, Hauser N, Lehman D, Pasumarti S, Paulsson M: Cartilage oligomeric matrix protein (COMP) is an abundant component of tendon. FEBS Lett. 1994, 354: 237-240. 10.1016/0014-5793(94)01134-6.CrossRefPubMed
13.
go back to reference Hesselstrand R, Kassner A, Heinegård D, Saxne T: COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker. Ann Rheum Dis. 2008, 67: 1242-1248.CrossRefPubMed Hesselstrand R, Kassner A, Heinegård D, Saxne T: COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker. Ann Rheum Dis. 2008, 67: 1242-1248.CrossRefPubMed
14.
go back to reference Gheita TA, Hussein H: Cartilage Oligomeric Matrix Protein (COMP) in systemic sclerosis (SSc): role in disease severity and subclinical rheumatoid arthritis overlap. Joint Bone Spine. 2012, 79: 51-56. 10.1016/j.jbspin.2011.02.022.CrossRefPubMed Gheita TA, Hussein H: Cartilage Oligomeric Matrix Protein (COMP) in systemic sclerosis (SSc): role in disease severity and subclinical rheumatoid arthritis overlap. Joint Bone Spine. 2012, 79: 51-56. 10.1016/j.jbspin.2011.02.022.CrossRefPubMed
15.
go back to reference Hesselstrand R, Andréasson K, Wuttge DM, Bozovic G, Scheja A, Saxne T: Increased serum COMP predicts mortality in SSc: results from a longitudinal study of interstitial lung disease. Rheumatology (Oxford). 2012, 51: 915-920. 10.1093/rheumatology/ker442.CrossRef Hesselstrand R, Andréasson K, Wuttge DM, Bozovic G, Scheja A, Saxne T: Increased serum COMP predicts mortality in SSc: results from a longitudinal study of interstitial lung disease. Rheumatology (Oxford). 2012, 51: 915-920. 10.1093/rheumatology/ker442.CrossRef
16.
go back to reference Riessen R, Fenchel M, Chen H, Axel DI, Karsch KR, Lawler J: Cartilage oligomeric matrix protein (thrombospondin-5) is expressed by human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2001, 21: 47-54. 10.1161/01.ATV.21.1.47.CrossRefPubMed Riessen R, Fenchel M, Chen H, Axel DI, Karsch KR, Lawler J: Cartilage oligomeric matrix protein (thrombospondin-5) is expressed by human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2001, 21: 47-54. 10.1161/01.ATV.21.1.47.CrossRefPubMed
17.
go back to reference Kalogerou A, Gelou E, Mountantonakis S, Settas L, Zafiriou E, Sakkas L: Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis. 2005, 64: 1233-1235. 10.1136/ard.2004.027094.PubMedCentralCrossRefPubMed Kalogerou A, Gelou E, Mountantonakis S, Settas L, Zafiriou E, Sakkas L: Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis. 2005, 64: 1233-1235. 10.1136/ard.2004.027094.PubMedCentralCrossRefPubMed
18.
go back to reference Higashi-Kuwata N, Jinnin M, Makino T, Fukushima S, Inoue Y, Muchemwa FC, Yonemura Y, Komohara Y, Takeya M, Mitsuya H, Ihn H: Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis. Arthritis Res Ther. 2010, 12: R128-10.1186/ar3066.PubMedCentralCrossRefPubMed Higashi-Kuwata N, Jinnin M, Makino T, Fukushima S, Inoue Y, Muchemwa FC, Yonemura Y, Komohara Y, Takeya M, Mitsuya H, Ihn H: Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis. Arthritis Res Ther. 2010, 12: R128-10.1186/ar3066.PubMedCentralCrossRefPubMed
19.
go back to reference Scala E, Pallotta S, Frezzolini A, Abeni D, Barbieri C, Sampogna F, De Pità O, Puddu P, Paganelli R, Russo G: Cytokine and chemokine levels in systemic sclerosis: relationship with cutaneous and internal organ involvement. Clin Exp Immunol. 2004, 138: 540-546.PubMedCentralCrossRefPubMed Scala E, Pallotta S, Frezzolini A, Abeni D, Barbieri C, Sampogna F, De Pità O, Puddu P, Paganelli R, Russo G: Cytokine and chemokine levels in systemic sclerosis: relationship with cutaneous and internal organ involvement. Clin Exp Immunol. 2004, 138: 540-546.PubMedCentralCrossRefPubMed
20.
go back to reference Gourh P, Arnett FC, Assassi S, Tan FK, Huang M, Diekman L, Mayes MD, Reveille JD, Agarwal SK: Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthritis Res Ther. 2009, 11: R147-10.1186/ar2821.PubMedCentralCrossRefPubMed Gourh P, Arnett FC, Assassi S, Tan FK, Huang M, Diekman L, Mayes MD, Reveille JD, Agarwal SK: Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthritis Res Ther. 2009, 11: R147-10.1186/ar2821.PubMedCentralCrossRefPubMed
21.
go back to reference Steen VD: Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005, 35: 35-42. 10.1016/j.semarthrit.2005.03.005.CrossRefPubMed Steen VD: Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005, 35: 35-42. 10.1016/j.semarthrit.2005.03.005.CrossRefPubMed
22.
go back to reference Senaldi G, Lupoli S, Vergani D, Black CM: Activation of the complement system in systemic sclerosis. Relationship to clinical severity. Arthritis Rheum. 1989, 32: 1262-1267. 10.1002/anr.1780321011.CrossRefPubMed Senaldi G, Lupoli S, Vergani D, Black CM: Activation of the complement system in systemic sclerosis. Relationship to clinical severity. Arthritis Rheum. 1989, 32: 1262-1267. 10.1002/anr.1780321011.CrossRefPubMed
23.
go back to reference Wild G, Watkins J, Ward AM, Hughes P, Hume A, Rowell NR: Complement activation in systemic sclerosis. J Clin Lab Immunol. 1990, 31: 39-41.PubMed Wild G, Watkins J, Ward AM, Hughes P, Hume A, Rowell NR: Complement activation in systemic sclerosis. J Clin Lab Immunol. 1990, 31: 39-41.PubMed
24.
go back to reference Sprott H, Muller-Ladner U, Distler O, Gay RE, Barnum SR, Landthaler M, Schölmerich J, Lang B, Gay S: Detection of activated complement complex C5b-9 and complement receptor C5a in skin biopsies of patients with systemic sclerosis (scleroderma). J Rheumatol. 2000, 27: 402-404.PubMed Sprott H, Muller-Ladner U, Distler O, Gay RE, Barnum SR, Landthaler M, Schölmerich J, Lang B, Gay S: Detection of activated complement complex C5b-9 and complement receptor C5a in skin biopsies of patients with systemic sclerosis (scleroderma). J Rheumatol. 2000, 27: 402-404.PubMed
25.
go back to reference Venneker GT, van den Hoogen FH, Boerbooms AM, Bos JD, Asghar SS: Aberrant expression of membrane cofactor protein and decay-accelerating factor in the endothelium of patients with systemic sclerosis. A possible mechanism of vascular damage. Lab Invest. 1994, 70: 830-835.PubMed Venneker GT, van den Hoogen FH, Boerbooms AM, Bos JD, Asghar SS: Aberrant expression of membrane cofactor protein and decay-accelerating factor in the endothelium of patients with systemic sclerosis. A possible mechanism of vascular damage. Lab Invest. 1994, 70: 830-835.PubMed
26.
go back to reference Happonen KE, Saxne T, Aspberg A, Mörgelin M, Heinegård D, Blom AM: Regulation of complement by cartilage oligomeric matrix protein allows for a novel molecular diagnostic principle in rheumatoid arthritis. Arthritis Rheum. 2010, 62: 3574-3583. 10.1002/art.27720.PubMedCentralCrossRefPubMed Happonen KE, Saxne T, Aspberg A, Mörgelin M, Heinegård D, Blom AM: Regulation of complement by cartilage oligomeric matrix protein allows for a novel molecular diagnostic principle in rheumatoid arthritis. Arthritis Rheum. 2010, 62: 3574-3583. 10.1002/art.27720.PubMedCentralCrossRefPubMed
27.
go back to reference Happonen KE, Saxne T, Geborek P, Andersson M, Bengtsson AA, Hesselstrand R, Heinegård D, Blom AM: Serum COMP-C3b complexes in rheumatic diseases and relation to anti-TNF-alpha treatment. Arthritis Res Ther. 2012, 14: R15-10.1186/ar3694.PubMedCentralCrossRefPubMed Happonen KE, Saxne T, Geborek P, Andersson M, Bengtsson AA, Hesselstrand R, Heinegård D, Blom AM: Serum COMP-C3b complexes in rheumatic diseases and relation to anti-TNF-alpha treatment. Arthritis Res Ther. 2012, 14: R15-10.1186/ar3694.PubMedCentralCrossRefPubMed
28.
go back to reference Souto-Carneiro MM, Burkhardt H, Muller EC, Hermann R, Otto A, Kraetsch HG, Sack U, König A, Heinegård D, Müller-Hermelink HK, Krenn V: Human monoclonal rheumatoid synovial B lymphocyte hybridoma with a new disease-related specificity for cartilage oligomeric matrix protein. J Immunol. 2001, 166: 4202-4208.CrossRefPubMed Souto-Carneiro MM, Burkhardt H, Muller EC, Hermann R, Otto A, Kraetsch HG, Sack U, König A, Heinegård D, Müller-Hermelink HK, Krenn V: Human monoclonal rheumatoid synovial B lymphocyte hybridoma with a new disease-related specificity for cartilage oligomeric matrix protein. J Immunol. 2001, 166: 4202-4208.CrossRefPubMed
29.
go back to reference Masi AT, Rodnan GP, Medsger TA, Altman RD: 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, 25: 581-590.CrossRef Masi AT, Rodnan GP, Medsger TA, Altman RD: 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, 25: 581-590.CrossRef
30.
go back to reference LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, Rowell N, Wollheim F: Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988, 15: 202-205.PubMed LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, Rowell N, Wollheim F: Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988, 15: 202-205.PubMed
31.
go back to reference Sjölander J, Westermark GT, Renström E, Blom AM: Islet amyloid polypeptide triggers limited complement activation and binds complement inhibitor C4b-binding protein, which enhances fibril formation. J Biol Chem. 2012, 287: 10824-10833. 10.1074/jbc.M111.244285.PubMedCentralCrossRefPubMed Sjölander J, Westermark GT, Renström E, Blom AM: Islet amyloid polypeptide triggers limited complement activation and binds complement inhibitor C4b-binding protein, which enhances fibril formation. J Biol Chem. 2012, 287: 10824-10833. 10.1074/jbc.M111.244285.PubMedCentralCrossRefPubMed
Metadata
Title
Cartilage oligomeric matrix protein-induced complement activation in systemic sclerosis
Authors
Kaisa E Otteby
Emelie Holmquist
Tore Saxne
Dick Heinegård
Roger Hesselstrand
Anna M Blom
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 6/2013
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar4410

Other articles of this Issue 6/2013

Arthritis Research & Therapy 6/2013 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.