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Cartilage oligomeric matrix protein specific antibodies are pathogenic.

ABSTRACT: INTRODUCTION: Cartilage oligomeric matrix protein (COMP) is a major non-collagenous component of cartilage. Earlier, we developed a new mouse model for rheumatoid arthritis using COMP. This study was undertaken to investigate the epitope specificity and immunopathogenicity of COMP-specific monoclonal antibodies (mAbs). METHODS: B cell immunodominant regions on the COMP molecule were measured with a novel enzyme-linked immunosorbent assay using mammalian expressed full-length mouse COMP as well as a panel of recombinant mouse COMP fragments. 18 mAbs specific to COMP were generated and the pathogenicity of mAbs was investigated by passive transfer experiments. RESULTS: B cell immunodominant epitopes were localized within 4 antigenic domains of the COMP but with preferential response to the epidermal growth factor (EGF)-like domain. Some of our anti-COMP mAbs showed interactions with the native form of COMP, which is present in cartilage and synovium. Passive transfer of COMP-specific mAbs enhanced arthritis when co-administrated with a sub-arthritogenic dose of a mAb specific to collagen type II. Interestingly, we found that a combination of 5 COMP mAbs was capable of inducing arthritis in naive mice. CONCLUSIONS: We have identified the specificities of mAbs to COMP and their contribution to the development of arthritis. These findings will further improve our understanding of the autoantibody mediated immunopathologies occurring widely in rheumatoid arthritis (RA), as well as in other autoimmune disorders.

SUBMITTER: Geng H

PROVIDER: S-EPMC3580587 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Cartilage oligomeric matrix protein specific antibodies are pathogenic.

Geng Hui H Nandakumar Kutty Selva KS Pramhed Anna A Aspberg Anders A Mattsson Ragnar R Holmdahl Rikard R

Arthritis research & therapy 20120820 4

<h4>Introduction</h4>Cartilage oligomeric matrix protein (COMP) is a major non-collagenous component of cartilage. Earlier, we developed a new mouse model for rheumatoid arthritis using COMP. This study was undertaken to investigate the epitope specificity and immunopathogenicity of COMP-specific monoclonal antibodies (mAbs).<h4>Methods</h4>B cell immunodominant regions on the COMP molecule were measured with a novel enzyme-linked immunosorbent assay using mammalian expressed full-length mouse C ...[more]

PMID: 22906101

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Project description:Background & aimsLiver fibrosis is characterized by significant accumulation of extracellular matrix (ECM) proteins, mainly fibrillar collagen-I, as a result of persistent liver injury. Cartilage oligomeric matrix protein (COMP) is largely found in the ECM of skeletal tissue. Increased COMP expression has been associated with fibrogenesis in systemic sclerosis, lung fibrosis, chronic pancreatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that COMP could induce fibrillar collagen-I deposition and participate in matrix remodeling thus contributing to the pathophysiology of liver fibrosis.MethodsThioacetamide (TAA) and carbon tetrachloride (CCl4) were used to induce liver fibrosis in wild-type (WT) and Comp-/- mice. In vitro experiments were performed with primary hepatic stellate cells (HSCs).ResultsCOMP expression was detected in livers from control WT mice and was upregulated in response to either TAA or CCl4-induced liver fibrosis. TAA-treated or CCl4-injected Comp-/- mice showed less liver injury, inflammation and fibrosis compared to their corresponding control WT mice. Challenge of HSCs with recombinant COMP (rCOMP) induced intra- plus extracellular collagen-I deposition and increased matrix metalloproteinases (MMPs) 2, 9 and 13, albeit similar expression of transforming growth factor beta (TGFβ) protein, in addition to Tgfβ, tumour necrosis factor alpha (Tnfα) and tissue inhibitor of metalloproteinases-1 (Timp1) mRNAs. We demonstrated that COMP binds collagen-I; yet, it does not prevent collagen-I cleavage by MMP1. Last, rCOMP induced collagen-I expression in HSCs via CD36 receptor signaling and activation of the MEK1/2-pERK1/2 pathway.ConclusionThese results suggest that COMP contributes to liver fibrosis by regulating collagen-I deposition.Lay summaryCartilage oligomeric matrix protein (COMP) induces fibrillar collagen-I deposition via the CD36 receptor signaling and activation of the MEK1/2-pERK1/2 pathway, and participates in extracellular matrix remodeling contributing to the pathophysiology of liver fibrosis.

Project description:PurposeCartilage oligomeric matrix protein (COMP) is known as a large pentameric glycoprotein, which interacts with various extracellular matrix proteins in tissues. COMP has been reported to play a role in multiple connective tissue disorders. Recently, elevated COMP levels have been found to be associated with increased tumor size, metastases, faster recurrence of cancer, and overall poorer survival in several cancers. However, the clinical importance of COMP in urothelial carcinoma remains unclear. We investigated the association between COMP expression and clinical outcomes in urothelial carcinoma.Patients and methodsIn this retrospective study, we collected urothelial carcinoma (UC) tissue from 340 upper urinary tract UC (UTUC) patients and 295 urinary bladder UC (UBUC) patients. Pearson's chi-square test, Kaplan-Meier analysis, and the multivariate Cox proportional hazards model was used to examine the relationship between COMP expression and patient characteristics, pathological findings, and patient survival, such as metastasis-free survival (MFS) and disease-specific survival (DSS).ResultsA total of 295 UBUC patients and 340 UTUC patients were recruited. The COMP mRNA level was significantly higher among invasive tumors (pT2-pT4) than in noninvasive tumors (pTa-T1) in UBUC groups (P < 0.01). COMP overexpression was associated with advanced T stage, nodal metastases, vascular invasion, perineural invasion, high histological grade, and high mitotic rate in both UBUC and UTUC cohorts. COMP overexpression was predictive of shorter DSS (hazard ratio [HR] in UBUC, 3.986, P < 0.001; in UTUC, 2.283, P = 0.027] and MFS (HR in UBUC, 6.813, P < 0.001; in UTUC, 4.070, P < 0.001). Kaplan-Meier analysis demonstrated high COMP expression associated with poor DSS and MFS in UTUC and UBUC groups (all P < 0.0001).ConclusionCOMP overexpression was linked to poor clinical prognosis and poor pathological features in UC. These results suggest COMP as a biomarker for UC.

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Cartilage oligomeric matrix protein specific antibodies are pathogenic.

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Cartilage oligomeric matrix protein specific antibodies are pathogenic.

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