Protein Modification by Deamidation Indicates Variations in Joint Extracellular Matrix Turnover
Departments of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.Journal of Biological Chemistry (Impact Factor: 4.57). 12/2011; 287(7):4640-51. DOI: 10.1074/jbc.M111.249649
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.
Article: Biological markers in osteoarthritis[Show abstract] [Hide abstract]
ABSTRACT: Osteoarthritis (OA) is considered as a chronic disease with a long "silent" period. The diagnosis is generally based on clinical symptoms and radiographic changes. However X-ray has a poor sensitivity and a relatively large precision error that does not allow an early detection of OA or the monitoring of joint damage progression. The limitations of the tools that are currently available for OA assessment have been the impetus to identify specific biological markers that reflect quantitative and dynamic variations in joint remodeling. Research has focused on the structural components of cartilage matrix, especially type II collagen degradation markers. In spite of a significant increase of some markers in individuals with early stage of OA, the large overlap with control subjects indicates that the current biomarkers used alone have limited diagnostic potential. However, the combination of specific markers seems to improve the prediction of disease progression at the individual level. Several types of treatment have been investigated but the lack of medications with definitively demonstrated chondroprotective activity has limited the assessment of the potential role of biomarkers for monitoring patients' responses to the treatment of OA. In this review, we will use the BIPED classification that appeared in 2006 for OA markers to describe the potential usage of a given marker . This article is part of a Special Issue entitled "Osteoarthritis".Bone 04/2012; 51(2):265-77. DOI:10.1016/j.bone.2012.04.001 · 3.97 Impact Factor
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ABSTRACT: Biomarkers provide useful diagnostic information by detecting cartilage degradation in osteoarthritis (OA), reflecting disease-relevant biological activity and predicting the course of disease progression. They also serve as surrogate endpoints in the drug discovery process. The aim of this narrative review was to focus on OA biomarker-related papers published between the osteoarthritis research society international (OARSI) 2011 meeting in San Diego and the OARSI 2012 meeting in Barcelona. The PubMed/MEDLINE and SciVerse Scopus bibliographic databases were searched using the keywords: 'biomarker' and 'osteoarthritis' and/or 'biomarker' and 'proteomics'. Ninety-eight papers were found with the keywords 'biomarker' and 'osteoarthritis'. Fifteen papers were found with the keywords 'biomarker' and 'proteomics'. Review articles were also included. The most relevant published studies focused on extracellular matrix (ECM) molecules in body fluids. Enrichment of the deamidated epitope of cartilage oligomeric matrix protein (D-COMP) suggests that OA disease progression is associated with post-translational modifications that may show specificity for particular joint sites. Fibulin-3 peptides (Fib3-1 and Fib3-2) have been proposed as potential biomarkers of OA along with follistatin-like protein 1 (FSTL1), a new serum biomarker with the capacity to reflect the severity of joint damage. The 'membrane attack complex' (MAC) component of complement has also been implicated in OA. Novel OA biomarkers are needed for sub-clinical disease diagnosis. Proteomic techniques are beginning to yield useful data and deliver new OA biomarkers in serum and urine. Combining biochemical markers with tissue and cell imaging techniques and bioinformatics (i.e., machine learning, clustering, data visualization) may facilitate the development of biomarker combinations enabling earlier detection of OA.Osteoarthritis and Cartilage 07/2012; 20(12):1451-64. DOI:10.1016/j.joca.2012.07.009 · 4.17 Impact Factor
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ABSTRACT: Objective: To evaluate the interaction of articular cartilage (AC) and subchondral bone (SB) through analysis of osteoarthritis (OA)-related genes of site-matched tissue. Design: We developed a novel method for isolating site-matched overlying AC and underlying SB from three and four regions of interest respectively from the human knee tibial plateau (n = 50). For each site, the severity of cartilage changes of OA were assessed histologically, and the severity of bone abnormalities were assessed by microcomputed tomography. An RNA isolation procedure was optimized that yielded high quality RNA from site-matched AC and SB tibial regions. Quantitative polymerase chain reaction (Q-PCR) analysis was performed to evaluate gene expression of 61 OA-associated genes for correlation with cartilage integrity and bone structure parameters. Results: A total of 27 (44%) genes were coordinately up- or down-regulated in both tissues. The expression levels of 19 genes were statistically significantly correlated with the severity of AC degeneration and changes of SB structure; these included: ADAMTS1, ASPN, BMP6, BMPER, CCL2, CCL8, COL5A1, COL6A3, COL7A1, COL16A1, FRZB, GDF10, MMP3, OGN, OMD, POSTN, PTGES, TNFSF11 and WNT1. Conclusions: These results provide a strategy for identifying targets whose modification may have the potential to ameliorate pathological alterations and progression of disease in both AC and SB simultaneously. In addition, this is the first study, to our knowledge, to overcome the major difficulties related to isolation of high quality RNA from site-matched joint tissues. We expect this method to facilitate advances in our understanding of the coordinated molecular responses of the whole joint organ.Osteoarthritis and Cartilage 12/2012; 21(3). DOI:10.1016/j.joca.2012.11.016 · 4.17 Impact Factor
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