Thrombin-cleaved Osteopontin Is Increased in Urine of Patients with Rheumatoid Arthritis

Shio, Kiori; Kobayashi, Hiroko; Asano, Tomohiko; Saito, Rie; Iwadate, Haruyo; Watanabe, Hiroshi; Sakuma, Hirofumi; Segawa, Tetsuya; Ohira, Hiromasa

doi:10.3899/jrheum.090582

Cited by 15 publications

(12 citation statements)

References 26 publications

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“…Consistent with previous observations [35], we found in the present study that OPN was closely associated with hsCRP levels independent of age, suggesting that OPN, as an impaortant inflammatory cytokine, may aggravate the inflammation status in diabetes mellitus. In addition, we demonstrated a significant association between plasma OPN levels and the presence and severity of CAD in diabetic patients, indicating that OPN may be critically involved in the inflammatory processes that take place within the vascular wall in diabetes.…”

Section: Discussionsupporting

confidence: 93%

“…Another study showed that the SVVYGLR sequence induces pro-MMP9 expression in isolated vascular smooth muscle cells, as well as in aortas from diabetic mice [36]. Clinically, N-half OPN levels are elevated in the synovial fluid, urine, and plasma of patients with rheumatoid arthritis [7,27,35], as well as in the vitreous fluid of those with diabetic retinopathy [26], indicating that this cytokine is involved in local inflammation. Because diabetes per se is an inflammatory process with increased cytokine levels and enhanced thrombin activity in the vascular wall [23], we hypothesized that N-half OPN may be associated with the development and severity of nephropathy and CAD in this setting.…”

Section: Discussionmentioning

confidence: 99%

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Plasma concentrations of osteopontin, but not thrombin-cleaved osteopontin, are associated with the presence and severity of nephropathy and coronary artery disease in patients with type 2 diabetes mellitus

Yan

Sano

Lü

et al. 2010

Cardiovasc Diabetol

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BackgroundThe aim of the present cross-sectional study was to assess possible associations between osteopontin (OPN), and thrombin-cleaved (N-half) OPN, and nephropathy and coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM).MethodsPlasma levels of OPN, N-half OPN, and high-sensitivity C-reactive protein (hsCRP) were determined in 301 diabetic patients with (n = 226) or without (n = 75) angiographically documented CAD (luminal diameter narrowing >50%), as well as in 75 non-diabetic controls with normal angiography. The estimated glomerular filtration rate (eGFR) was calculated in all patients.ResultsPlasma levels of OPN and hsCRP were significantly higher in patients with T2DM compared with controls. In addition, there was a higher occurrence of moderate renal insufficiency and lower eGFR in patients with T2DM (all P < 0.01). T2DM patients in whom OPN levels were greater than the median value had higher serum creatinine levels, a greater prevalence of mild or moderate renal insufficiency, a higher incidence of CAD, and lower eGFR (all P < 0.05) than T2DM patients in whom OPN levels were the same as or lower than the median value. However, there were no differences in these parameters when patients were stratified according to plasma N-half OPN levels. Furthermore, there was a significant correlation between OPN, but not N-half OPN, and the severity of nephropathy and CAD in diabetes. After adjustment for potential confounders and treatments, multiple linear regression analysis demonstrated an independent association between OPN, but not N-half OPN, and eGFR. Multivariate logistic regression revealed that higher OPN levels conferred a fourfold greater risk of renal insufficiency and CAD in patients with T2DM.ConclusionsThe results of the present study demonstrate that there is an independent association between plasma levels of OPN, but not N-half OPN, and the presence and severity of nephropathy and CAD in diabetes.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Plasma concentrations of osteopontin, but not thrombin-cleaved osteopontin, are associated with the presence and severity of nephropathy and coronary artery disease in patients with type 2 diabetes mellitus

Yan

Sano

Lü

et al. 2010

Cardiovasc Diabetol

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“…Several other members of class 1 have been previously examined as biomarkers of renal and urological health including calbindin [23], clusterin [24]–[26], A1A [27]–[29], and MPO [30]. Urine levels of OPN, a multifunctional protein implicated in bone remodeling and inflammation, have been associated with rheumatoid arthritis and ovarian cancer [4], [31]. The list of biomarkers included in classes 2 and 3 illustrate the diverse potential of urine biomarkers and include proteins involved in inflammation, apoptosis, growth regulation, metabolism, endocrine signaling and numerous additional processes.…”

Section: Discussionmentioning

confidence: 99%

An Extensive Targeted Proteomic Analysis of Disease-Related Protein Biomarkers in Urine from Healthy Donors

et al. 2013

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The analysis of protein biomarkers in urine is expected to lead to advances in a variety of clinical settings. Several characteristics of urine including a low-protein matrix, ease of testing and a demonstrated proteomic stability offer distinct advantages over current widely used biofluids, serum and plasma. Improvements in our understanding of the urine proteome and in methods used in its evaluation will facilitate the clinical development of urinary protein biomarkers. Multiplexed bead-based immunoassays were utilized to evaluate 211 proteins in urines from 103 healthy donors. An additional 25 healthy donors provided serial urine samples over the course of two days in order to assess temporal variation in selected biomarkers. Nearly one-third of the evaluated biomarkers were detected in urine at levels greater than 1ng/ml, representing a diverse panel of proteins with respect to structure, function and biological role. The presence of several biomarkers in urine was confirmed by western blot. Several methods of data normalization were employed to assess impact on biomarker variability. A complex pattern of correlations with urine creatinine, albumin and beta-2-microglobulin was observed indicating the presence of highly specific mechanisms of renal filtration. Further investigation of the urinary protein biomarkers identified in this preliminary study along with a consideration of the underlying proteomic trends suggested by these findings should lead to an improved capability to identify candidate biomarkers for clinical development.

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“…Previous studies concerning OPN have mostly focused on OPN production in different diseases and disease severities, i.e. increased OPN levels have been shown to correlate with a more severe disease phenotype [24, 25, 28]. OPN’s phosphorylation is known to exert a critical effect on a wide range of its cytokine properties from inhibition of biomineralization to osteoclast activation and pathogenesis of inflammatory diseases; this is because phosphorylation is required for its key functions, such as working as a proinflammatory cytokine [10–12, 26, 29–31].…”

Section: Discussionmentioning

confidence: 99%

Increased amount of phosphorylated proinflammatory osteopontin in rheumatoid arthritis synovia is associated to decreased tartrate-resistant acid phosphatase 5B/5A ratio

et al. 2017

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BackgroundOsteopontin (OPN) is an immunoregulatory protein which production increases in both rheumatoid arthritis (RA) and osteoarthritis (OA). Phosphorylated osteopontin (Phospho-OPN) is known to increase macrophage and osteoclast activation, this process is controlled by extracellular tartrate-resistant acid phosphatase (TRAcP), also a biomarker for RA. Here, we evaluated the phosphorylation status of OPN in RA and OA synovia, as well as its correlation with TRAcP isoforms.MethodsSynovial tissue and fluid were obtained from 24 RA (14 seropositive and 10 seronegative) and 24 OA patients. Western blotting was used to analyze the extent of OPN phosphorylation. TRAcP isoforms were measured in synovial fluid using ELISA; immunohistochemistry assessed the distribution of OPN and TRAcP expressing cells in the synovial tissue, especially distinguishing between the TRAcP isoforms.ResultsFull-length OPN was more phosphorylated in RA than in OA (p<0.05). The thrombin cleaved C-terminal end of OPN was also more phosphorylated in RA (p<0.05). RA patients had a lower concentration of TRAcP 5B and higher concentration of less active 5A in their synovial fluid compared to OA patients. The TRAcP 5B/5A ratio was decreased in RA and correlated negatively with the amount of phospho-OPN (p<0.05). TRAcP positive cells for both isoforms were found all along the synovial lining; OPN antibody staining was localized in the extracellular matrix.ConclusionOur data suggests that in RA the synovial fluid contains insufficient amounts of TRAcP 5B which increase levels of the proinflammatory phospho-OPN. This may lead to increased macrophage and osteoclast activation, resulting in the increased local inflammation and bone resorption present in RA joints.

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Thrombin-cleaved Osteopontin Is Increased in Urine of Patients with Rheumatoid Arthritis

Abstract: Our results suggest that urine levels of the thrombin-cleaved isoform of OPN may reflect the severity of active inflammatory arthritis in patients with RA.

Cited by 15 publications

References 26 publications

Plasma concentrations of osteopontin, but not thrombin-cleaved osteopontin, are associated with the presence and severity of nephropathy and coronary artery disease in patients with type 2 diabetes mellitus

Plasma concentrations of osteopontin, but not thrombin-cleaved osteopontin, are associated with the presence and severity of nephropathy and coronary artery disease in patients with type 2 diabetes mellitus

An Extensive Targeted Proteomic Analysis of Disease-Related Protein Biomarkers in Urine from Healthy Donors

Increased amount of phosphorylated proinflammatory osteopontin in rheumatoid arthritis synovia is associated to decreased tartrate-resistant acid phosphatase 5B/5A ratio

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