Abstract
As extracellular proteins age, they undergo and accumulate nonenzymatic post-translational modifications that cannot be repaired. We hypothesized that these could be used to systemically monitor loss of extracellular matrix due to chronic arthritic diseases such as osteoarthritis (OA). To test this, we predicted sites of deamidation in cartilage oligomeric matrix protein (COMP) and confirmed, by mass spectroscopy, the presence of deamidated (Asp(64)) and native (Asn(64)) COMP epitopes (mean 0.95% deamidated COMP (D-COMP) relative to native COMP) in cartilage. An Asp(64), D-COMP-specific ELISA was developed using a newly created monoclonal antibody 6-1A12. In a joint replacement study, serum D-COMP (p = 0.017), but not total COMP (p = 0.5), declined significantly after replacement demonstrating a joint tissue source for D-COMP. In analyses of 450 participants from the Johnston County Osteoarthritis Project controlled for age, gender, and race, D-COMP was associated with radiographic hip (p < 0.0001) but not knee (p = 0.95) OA severity. In contrast, total COMP was associated with radiographic knee (p < 0.0001) but not hip (p = 0.47) OA severity. D-COMP was higher in soluble proteins extracted from hip cartilage proximal to OA lesions compared with remote from lesions (p = 0.007) or lesional and remote OA knee (p < 0.01) cartilage. Total COMP in cartilage did not vary by joint site or proximity to the lesion. This study demonstrates the presence of D-COMP in articular cartilage and the systemic circulation, and to our knowledge, it is the first biomarker to show specificity for a particular joint site. We believe that enrichment of deamidated epitope in hip OA cartilage indicates a lesser repair response of hip OA compared with knee OA cartilage.
Highlights
Can be repaired or the protein replaced [1]; in the extracellular milieu, where no repair mechanisms exist, nonenzymatic modifications can accumulate in a time-dependent manner in proteins whose turnover is slow
We further demonstrated the presence of deamidated cartilage oligomeric matrix protein (COMP) (D-COMP) in articular cartilage and the systemic circulation, an enrichment of this epitope in hip articular cartilage, and a correlation of this epitope in the systemic circulation with hip OA severity
Concentrations of D-COMP in Hip Cartilage Exceeded Those of Knee Cartilage—To better understand the results from the Johnston County OA Project (JoCo OA) cohort and the relationship between D-COMP and hip OA, we investigated the amount of D-COMP and total COMP in guanidine HCl (Gdn-HCl)-extracted soluble protein from OA hip (n ϭ 12) and knee cartilage samples (n ϭ 16) collected as waste surgical tissue at the time of joint arthroplasty
Summary
Can be repaired or the protein replaced [1]; in the extracellular milieu, where no repair mechanisms exist, nonenzymatic modifications can accumulate in a time-dependent manner in proteins whose turnover is slow. One form of nonenzymatic protein modification, deamidation, is believed to be a mechanism of amino acid damage and aging in numerous proteins [2] and a variety of tissues [2, 3]. 26 (42%) 71.3 Ϯ 10.0 (52–90ϩ) 11 11 15 N/A degree of extracellular matrix loss during osteoarthritis (OA).2 To test this hypothesis, we identified a novel protein modification due to deamidation in cartilage oligomeric matrix protein (COMP). We further demonstrated the presence of deamidated COMP (D-COMP) in articular cartilage and the systemic circulation, an enrichment of this epitope in hip articular cartilage, and a correlation of this epitope in the systemic circulation with hip OA severity
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