| 1. |
- Groen, Solveig Skovlund, et al.
(författare)
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A serological type II collagen neoepitope biomarker reflects cartilage breakdown in patients with osteoarthritis
- 2021
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Ingår i: Osteoarthritis and Cartilage Open. - : Elsevier BV. - 2665-9131. ; 3:4
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: There is an unmet medical need for biomarkers in OA which can be applied in clinical drug development trials. The present study describes the development of a specific and robust assay measuring type II collagen degradation (T2CM) and discusses its potential as a noninvasive translational biomarker. Methods: A type II collagen specific neoepitope (T2CM) was identified by mass spectrometry and monoclonal antibodies were raised towards the epitope, employed in a chemiluminescence immunoassay. T2CM was assessed in bovine cartilage explants with or without MMP-13 inhibitor, and explant supernatants were analyzed by Western blot. T2CM was measured in plasma samples from one study (n = 48 patients) where OA patients were referred to total knee replacement (TKR). Additionally, T2CM was quantified in serum from OA patients receiving salmon calcitonin treatment (sCT) (n = 50) compared to placebo (n = 57). Results: The T2CM assay was technically robust (13/4 % inter/intra-variation) and specific for the type II collagen fragment cleaved by MMP-1 and -13. The MMP-13 inhibitor reduced the T2CM release from bovine cartilage explants receiving catabolic treatment. These results were confirmed by Western blot. In human end-stage OA patients (scheduled for TKR), the T2CM levels were elevated compared to moderate OA (p<0.004). The OA patients receiving sCT had lower levels of T2CM compared to placebo group after 1, 6, and 24 months of treatment (p = 0.0285, p = 0.0484, p = 0.0035). Conclusions: To our knowledge, T2CM is the first technically robust serological biomarker assay which has shown biological relevance in ex vivo models and OA cohorts. This suggests that T2CM may have potential as a translational biomarker for cartilage degradation.
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| 2. |
- Al-Sharify, Dania, et al.
(författare)
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Increased proteolytic cleavage of osteoglycin is associated with a stable plaque phenotype and lower risk of cardiovascular events
- 2022
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 355, s. 8-14
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Extracellular matrix (ECM) remodeling is one of the key components in the formation of vulnerable atherosclerotic plaques and cardiovascular events. We recently showed that the full-length ECM-proteoglycan osteoglycin was associated with plaque vulnerability and future cardiovascular events. In the present study, we aimed to investigate the association of cleaved osteoglycin with plaque phenotype. Methods: Two-hundred human carotid plaques were analyzed by immunohistochemistry. Cleaved osteoglycin and active caspase-3 were assessed by ELISA. ECM components (collagen, elastin and glycosaminoglycans) were assessed by colorimetric assays in plaque tissue homogenates. Matrix metalloproteinases (MMPs) were assessed using Milliplex. MMP-cleavage of osteoglycin and its effect on apoptosis were studied in vitro. Cardiovascular events were recorded during follow-up using national registries. Results: Plaque levels of cleaved osteoglycin were significantly higher in asymptomatic plaques and correlated to α-actin plaque area, collagen, elastin and inversely to lipids, active. caspase-3 and a histological vulnerability index. Cleaved osteoglycin correlated to several MMPs, especially MMP-12, which was also shown to cleave osteoglycin in vitro. In vitro cleavage of osteoglycin was also associated with less smooth muscle cell apoptosis. Patients with high plaque levels of cleaved osteoglycin had a significantly lower risk to suffer from future cardiovascular events. Conclusions: The current study shows that cleaved osteoglycin is associated with a stable plaque phenotype and lower risk for future cardiovascular events. Potentially due to reduced cell apoptosis and ability to retain LDL. These results indicate that targeting the cleavage of osteoglycin may be a potential therapeutic strategy to stabilize plaques.
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| 3. |
- Genovese, Federica, et al.
(författare)
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Plasma levels of PRO-C3, a type III collagen synthesis marker, are associated with arterial stiffness and increased risk of cardiovascular death
- 2024
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Ingår i: Atherosclerosis. - 0021-9150. ; 388
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: The N-terminal propeptide of type III collagen (PRO-C3) assay measures a pro-peptide released during type III collagen synthesis, an important feature of arterial stiffening and atherogenesis. There is a clinical need for improved non-invasive, cheap and easily accessible methods for evaluating individuals at risk of cardiovascular disease (CVD). In this study, we investigate the potential of using circulating levels of PRO-C3 to mark the degree of vascular stenosis and risk of cardiovascular events. Methods: Baseline plasma levels of PRO-C3 were measured by ELISA in subjects belonging to the SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort (N = 1354). Associations between PRO-C3 levels with vascular characteristics, namely stiffness and stenosis, and risk of future cardiovascular events were explored. Subjects were followed up after a median of 35 months (interquartile range 34–36 months), with recorded outcomes cardiovascular death and all-cause mortality. Results: We found a correlation between PRO-C3 levels and pulse wave velocity (rho 0.13, p = 0.000009), a measurement of arterial stiffness. Higher PRO-C3 levels were also associated with elevated blood pressure (rho 0.07, p = 0.014), as well as risk of cardiovascular mortality over a three-year follow-up period (OR 1.56, confidence interval 1.008–2.43, p = 0.046). Conclusions: Elevated circulating PRO-C3 levels are associated with arterial stiffness and future cardiovascular death, in the SUMMIT cohort, suggesting a potential value of PRO-C3 as a novel marker for declining vascular health.
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| 4. |
- Groen, Solveig Skovlund, et al.
(författare)
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Exploring IL-17 in spondyloarthritis for development of novel treatments and biomarkers
- 2021
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Ingår i: Autoimmunity Reviews. - : Elsevier BV. - 1568-9972. ; 20:3
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Forskningsöversikt (refereegranskat)abstract
- Spondyloarthritis (SpA) is an umbrella term describing a family of chronic inflammatory rheumatic diseases. These diseases are characterised by inflammation of the axial skeleton, peripheral joints, and entheseal insertion sites throughout the body which can lead to structural joint damage including formation of axial syndesmophytes and peripheral osteophytes. Genetic evidence, preclinical and clinical studies indicate a clear role of interleukin (IL)- 23 and IL-17 as mediators in SpA pathogenesis. Targeting the IL-23/−17 pathways seems an efficient strategy for treatment of SpA patients, and despite the remaining challenges the pathway holds great promise for further advances and improved therapeutic opportunities. Much research is focusing on serological markers and imaging strategies to correctly diagnose patients in the early stages of SpA. Biomarkers may facilitate personalised medicine tailored to each patient's specific disease to optimise treatment efficacy and to monitor therapeutic response. This narrative review focuses on the IL-17 pathway in SpA-related diseases with emphasis on its role in pathogenesis, current approved IL-17 inhibitors, and the need for biomarkers reflecting core disease pathways for early diagnosis and measurement of disease activity, prognosis, and response to therapy.
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| 5. |
- Hammaréus, Filip, 1998-, et al.
(författare)
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Plasma type I collagen α1 chain in relation to coronary artery disease : findings from a prospective population-based cohort and an acute myocardial infarction prospective cohort in Sweden.
- 2023
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To investigate the association between type I collagen α1 chain (COL1α1) levels and coronary artery disease (CAD) by using absolute quantification in plasma. Also, to investigate the correlates of COL1α1 to clinical characteristics and circulating markers of collagen metabolism.DESIGN: Life conditions, Stress and Health (LSH) study: prospective cohort study, here with a nested case-control design.Assessing Platelet Activity in Coronary Heart Disease (APACHE) study: prospective cohort study.SETTING: LSH: primary care setting, southeast Sweden.APACHE: cardiology department, university hospital, southeast Sweden.PARTICIPANTS: LSH: 1007 randomly recruited individuals aged 45-69 (50% women). Exclusion criteria was serious disease. After 13 years of follow-up, 86 cases with primary endpoint were identified and sex-matched/age-matched to 184 controls.APACHE: 125 patients with myocardial infarction (MI), 73 with ST-elevation MI and 52 with non-ST-elevation MI.EXCLUSION CRITERIA: Intervention study participation, warfarin treatment and short life expectancy.PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was the association between baseline COL1α1 and first-time major event of CAD, defined as fatal/non-fatal MI or coronary revascularisation after 13 years. Secondary outcomes were the association between the collagen biomarkers PRO-C1 (N-terminal pro-peptide of type I collagen)/C1M (matrix metalloproteinase-mediated degradation of type I collagen) and CAD; temporal change of COL1α1 after acute MI up to 6 months and lastly, correlates between COL1α1 and patient characteristics along with circulating markers of collagen metabolism.RESULTS: COL1α1 levels were associated with CAD, both unadjusted (HR=0.69, 95% CI=0.56 to 0.87) and adjusted (HR=0.55, 95% CI=0.41 to 0.75). PRO-C1 was associated with CAD, unadjusted (HR=0.62, 95% CI=0.47 to 0.82) and adjusted (HR=0.61, 95% CI=0.43 to 0.86), while C1M was not. In patients with MI, COL1α1 remained unchanged up to 6 months. COL1α1 was correlated to PRO-C1, but not to C1M.CONCLUSIONS: Plasma COL1α1 was independently and inversely associated with CAD. Furthermore, COL1α1 appeared to reflect collagen synthesis but not degradation. Future studies are needed to confirm whether COL1α1 is a clinically useful biomarker of CAD.
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| 6. |
- Nielsen, Signe Holm, et al.
(författare)
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Markers of basement membrane remodeling are associated with higher mortality in patients with known atherosclerosis
- 2018
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 7:21
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Tidskriftsartikel (refereegranskat)abstract
- Background-Patients with atherosclerosis have a high risk of cardiovascular events and death. Atherosclerosis is characterized by accumulation of lipids, cells and extracellular matrix proteins in the intima. We hypothesized that dysregulated remodeling of the basement membrane proteins may be associated with clinical outcomes in patients with atherosclerosis. Methods and Results-Neoepitope fragments of collagen type IV (C4M) and laminin (LG1M) were assessed by ELISAs in serum from 787 endarterectomy patients. Matrix metalloproteinases were measured using proximity extension assay and correlated to C4M and LG1M levels using Spearman correlations. A total of 473 patients were followed up for 6 years using national registers, medical charts, and telephone interviews. The incidence of cardiovascular events, cardiovascular mortality, and all-cause mortality were associated to levels of C4M and LG1M using Kaplan–Meier curves and Cox regression analyses. A total of 101 patients had cardiovascular events, 39 died of cardiovascular mortality, and 64 patients died from all-cause mortality. C4M levels were increased in patients with symptomatic carotid atherosclerotic disease before surgery (P=0.048). High C4M and LG1M levels were associated with increased risk of all-cause mortality (P=0.020 and 0.031, respectively) and predicted all-cause death together with glomerular filtration rate and diabetes mellitus. Conclusions-High LG1M and C4M levels were associated with all-cause mortality, together with glomerular filtration rate and diabetes mellitus. These novel biomarkers need further evaluation but might be tools to identify high-risk patients.
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| 7. |
- Sinkeviciute, Dovile, et al.
(författare)
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A novel biomarker of MMP-cleaved prolargin is elevated in patients with psoriatic arthritis
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Psoriatic arthritis (PsA) is a chronic musculoskeletal inflammatory disease found in up to 30% of psoriasis patients. Prolargin—an extracellular matrix (ECM) protein present in cartilage and tendon—has been previously shown elevated in serum of patients with psoriasis. ECM protein fragments can reflect tissue turnover and pathological changes; thus, this study aimed to develop, validate and characterize a novel biomarker PROM targeting a matrix metalloproteinase (MMP)-cleaved prolargin neo-epitope, and to evaluate it as a biomarker for PsA. A competitive ELISA was developed with a monoclonal mouse antibody; dilution- and spiking-recovery, inter- and intra-variation, and accuracy were evaluated. Serum levels were evaluated in 55 healthy individuals and 111 patients diagnosed with PsA by the CASPAR criteria. Results indicated that the PROM assay was specific for the neo-epitope. Inter- and intra- assay variations were 11% and 4%, respectively. PROM was elevated (p = 0.0003) in patients with PsA (median: 0.24, IQR: 0.19–0.31) compared to healthy controls (0.18; 0.14–0.23) at baseline. AUROC for separation of healthy controls from PsA patients was 0.674 (95% CI 0.597–0.744, P < 0.001). In conclusion, MMP-cleaved prolargin can be quantified in serum by the PROM assay and has the potential to separate patients with PsA from healthy controls.
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| 8. |
- Tengryd, Christoffer, et al.
(författare)
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The proteoglycan mimecan is associated with carotid plaque vulnerability and increased risk of future cardiovascular death
- 2020
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 313, s. 88-95
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: A vulnerable plaque is an atherosclerotic plaque that is rupture-prone with a higher risk to cause cardiovascular symptoms such as myocardial infarction or stroke. Mimecan or osteoglycin is a small leucine-rich proteoglycan, important for collagen fibrillogenesis, that has been implicated in atherosclerotic disease, yet the role of mimecan in human atherosclerotic disease remains unknown. Methods: 196 human atherosclerotic carotid plaques were immunostained for mimecan. Smooth muscle cells, macrophages and intraplaque haemorrhage were also measured with immunohistochemistry. Neutral lipids were stained with Oil Red O and calcium deposits were quantified. Plaque homogenate levels of MCP-1, IL-6 and MIP-1β were measured using a Proximity Extension Assay and MMP-9 levels were measured using Mesoscale. Glycosaminoglycans, collagen and elastin were assessed by colorimetric assays and TGF-β1, β2 and β3 were measured using a multiplex assay. Mimecan gene expression in THP-1 derived macrophages was quantified by qPCR and protein expression in vitro was visualized with immunofluorescence. Cardiovascular events were registered using medical charts and national registers during follow-up. Results: Mimecan correlated positively with plaque area of lipids, macrophages, intraplaque haemorrhage and inversely with smooth muscle cell staining. Mimecan also correlated positively with plaque levels of MMP-9 and MCP-1. Mimecan was upregulated in THP-1 derived macrophages upon stimulation with MCP-1. Patients with high levels of mimecan (above median) had higher risk for cardiovascular death. Conclusions: This study indicates that mimecan is associated with a vulnerable plaque phenotype, possibly regulated by plaque inflammation. In line, plaque levels of mimecan independently predict future cardiovascular death.
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