Markers Of Collagen Degradation Research Articles

Osteoclast indices in osteogenesis imperfecta: systematic review and meta-analysis.

Osteogenesis imperfecta (OI) is a rare bone fragility disorder caused by mutations in genes encoding collagen type I or that affect its processing. Alterations in osteoclasts were suggested to contribute to OI pathophysiology. We aimed to systematically identify studies reporting measures of osteoclast formation and function in patients and mouse models of OI, to quantify OI-induced changes. The systematic search of Medline, Ovid, and Web of Science identified 798 unique studies. After screening, we included 23 studies for meta-analysis, reporting osteoclast parameters in 310 patients with OI of 9 different types and 16 studies reporting osteoclast parameters in 406 animals of 11 different OI mouse models. The standardized mean difference with 95% confidence interval (CI) was used as the effect size, and random-effects meta-analysis was performed. In patients with OI, collagen degradation markers were significantly higher compared with age-matched controls, with an effect size of 1.23 (CI: 0.36, 2.10]. Collagen degradation markers were the most elevated in the 3- to 7-year-old age group and in patients with more severe forms of OI. Bone histomorphometry demonstrated the trends for higher osteoclast numbers (1.16; CI: -0.22, 2.55) and osteoclast surface (0.43; CI: -0.63, 1.49), and significantly higher eroded surface (3.24; CI: 0.51, 5.96) compared with age-matched controls. In OI mice, meta-analysis demonstrated significant increases in collagen degradation markers (1.59; CI: 1.07, 2.11), in osteoclast numbers (0.94; CI: 0.50, 1.39), osteoclast surface (0.73; CI: 0.22, 1.23), and eroded surface (1.31; CI: 0.54, 2.08). The largest differences were in OI mice with the mutations in Col1a1 and Col1a2 genes. There were no differences between males and females in clinical or animal studies. Quantitative estimates of changes in osteoclast indices and their variance for patients with OI are important for planning future studies. We confirmed that similar changes are observed in mice with OI, supporting their translational utility.

Anti-inflammatory effects of polydeoxyribonucleotide and adipose tissue-derived mesenchymal stem cells in a canine cell model of osteoarthritis.

A relatively new therapeutic agent for osteoarthritis (OA), polydeoxyribonucleotide (PDRN), shows potential in treating human OA due to its regenerative and anti-inflammatory effects. However, studies on PDRN for canine OA are limited, and no study has investigated their use with mesenchymal stem cells (MSCs) conventionally used for OA treatment. This study aimed to evaluate the potential of PDRN and explore its combined effect with adipose tissue-derived MSCs (AdMSCs) in treating canine OA. To study the impact of PDRN, canine chondrocytes, synoviocytes, and AdMSCs were exposed to various PDRN concentrations, and viability was assessed using cell counting kit-8. The OA model was created by treating chondrocytes and synoviocytes with lipopolysaccharide, followed by treatment under three different conditions: PDRN alone, AdMSCs alone, and a combination of PDRN and AdMSCs. Using real-time quantitative polymerase chain reaction, the anti-inflammatory effects and mechanisms were investigated by quantitatively assessing pro-inflammatory cytokines, collagen degradation markers, adenosine A2a receptor (ADORA2A), and nuclear factor-kappa B. PDRN alone and combined with AdMSCs significantly reduced the expression of pro-inflammatory cytokines and collagen degradation markers in an OA model. PDRN promoted AdMSC proliferation and upregulated ADORA2A expression. AdMSCs exhibited comprehensive anti-inflammatory effects through paracrine effects, and both substances reduced inflammatory gene expression through different mechanisms, potentially enhancing therapeutic effects. The results indicate that PDRN is a safe and effective anti-inflammatory material that can be used independently or as an adjuvant for AdMSCs. Although additional research is necessary, this study is significant because it provides a foundation for future research at the cellular level.

Effects of nintedanib on circulating biomarkers of idiopathic pulmonary fibrosis

BackgroundBiomarkers that change in response to nintedanib in subjects with idiopathic pulmonary fibrosis (IPF) would be valuable. We investigated the effects of nintedanib on circulating biomarkers in subjects with IPF in the INMARK trial.MethodsSubjects with IPF were randomised 1:2 to receive nintedanib 150 mg bid or placebo for 12 weeks, after which all patients received open-label nintedanib for 40 weeks. Fold changes in adjusted mean levels of circulating biomarkers were analysed using a linear mixed model for repeated measures.Results346 subjects were treated (116 randomised to nintedanib, 230 to placebo). SP-D and CA-125, markers of epithelial injury, decreased in subjects treated with nintedanibversusplacebo. Fold changes from baseline in SP-D at week 12 corresponded to a 4% decrease and 3% increase in the nintedanib and placebo groups, respectively (ratio 0.94 [95% CI: 0.89, 0.99]; p=0.024). Fold changes in CA-125 at week 12 corresponded to a 22% decrease and 4% increase in the nintedanib and placebo groups, respectively (ratio 0.75 [95% CI: 0.71, 0.81]; p<0.0001). A mediation analysis suggested that 42.1% of the effect of nintedanib on change in FVC over 12 weeks was attributable to the change in CA-125. A small increase in C3A and a small decrease in C3M, markers of extracellular matrix turnover, were observed in subjects treated with nintedanibversusplacebo.ConclusionsEffects of nintedanib on circulating markers of epithelial dysfunction and collagen degradation, most notably CA-125, were observed in patients with IPF.

ICTP concentration in cervical-vaginal fluid as a potential marker of membrane collagen degradation before labor.

Numerous physical and chemical processes lead to rupture of membranes. Within the fetal membranes there are numerous types of metalloproteinases, which cause collagen type I degradation. The C-terminal telopeptide of colagen type I (ICTP) is the breakdown product of type I collagen. The aim of the study was to determine whether ICTP is secreted into the vaginal-cervical fluid (VCF) in the case of physiological rupture of the membranes of the fetus before delivery. The study was conducted in March 2021 at the Department of Obstetrics and Perinatology of the Jagiellonian University in Cracow, Poland. Twenty-three cases were included in the study. During routine gynecological examination with the use of specula, VCF was collected twice in a volume of 50 µL. The obtained material was then subjected to enzyme immunoassay using the Human C-telopeptide of type I collagen (ICTP) ELISA Kit (Catalog Number. CSB-E10363h). The concentration of ICTP in the sample was calibrated. The concentration range that the device can detect was 25 ng /mL-800 ng/mL. The presence of ICTP in the VCF was confirmed. The minimum concentration was 43.72 ng/mL, the maximum was 762.59, in five cases the concentration was outside the maximum scale of the device. ICTP was confirmed in the VCF of pregnant women before physiological delivery. Further studies are required to accurately evaluate ICTP as a marker of the processes of collagen degradation in fetal membranes in the mechanism of physiological labor and premature rupture of the membranes.

Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis.

Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events. Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test. Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001). Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.

Markers of Collagen Degradation in Remodeling and Diastolic Dysfunction of Left Ventricle in Patients with Arterial Hypertension

Introduction. Myocardial remodeling is a consequence or predictor of several cardiovascular diseases. The key process in myocardial remodeling is the degradation of collagen fibers, mediated by the activity of matrix metalloproteinases and their tissue inhibitor.The aim of this study was to evaluate serum levels of matrix metalloproteinase type 9 and tissue inhibitor of matrix metalloproteinase type 1 in female patients with arterial hypertension, myocardial remodeling, and diastolic dysfunction.Materials and methods. A cross-sectional study that included 84 postmenopausal women. All patients underwent echocardiography. Left ventricular remodeling was assessed according to Ganau classification, and diastolic function was evaluated using transmittal flow parameters. Serum analysis included the determination of MMP-9 and TIMP-1 levels using an enzyme-linked immunosorbent assay.Results. The median concentration of MMP-9 in the sample was 2 295.00 (923.60–4 114.00) ng/ml, TIMP — 1–17 010.00 (16 780.00–17 170.00) ng/ml. When evaluating the echocardiographic parameters of the patients included in the study, changes were revealed that indicate structural and functional remodeling of the LV and DD. 29 patients (35 %) had normal geometry, 6 patients (7 %) had concentric myocardial remodeling, 21 patients (25 %) had concentric myocardial hypertrophy, 28 cases (33 %) had eccentric myocardial hypertrophy. Statistically significant changes in the activity of MMP-9 and TIMP-1 were revealed in patients with various structural and geometric variants of remodeling. DD was detected in all patients included in the study: I degree was detected in 25 patients (30 %), II degree was determined in 59 cases (70 %). Using one-way analysis of variance, statistically significant differences in the level of MMP-9 in patients with grades I and II DD were determined. MMP-9 and MMP-9/TIMP-1 in patients with grade II DD are significantly higher than in patients with grade I.Discussion. Under pathophysiological conditions, the proteolytic properties of MMP-9 contribute to the stimulation of the immune response, initiating pathogenesis and aggravating the progression of the disease. Evaluation of the activity of MMP-9 and TIMP-1 in patients with arterial hypertension may be a marker of myocardial remodeling.Conclusion. An increase in the activity of matrix metalloproteinase type 9 and a decrease in the activity of a tissue inhibitor of matrix metalloproteinases type 1 were revealed in patients with arterial hypertension, myocardial remodeling and LV diastolic dysfunction. The level of MMP-9 is associated with the degree of diastolic dysfunction and the structural-geometric type of LV remodeling.

Hemodynamics and plasma biomarkers in individuals with mild-to-moderate ascending aortic dilatation and tricuspid aortic valves

Abstract Background Ascending aortic (AA) dilatation is a silent disease that requires frequent follow-up measurements of the AA diameter. Unfortunately, the AA diameter is an insufficient predictor of future growth and complications. Hemodynamic and circulating biomarkers represent promising ways of improving the risk stratification in AA dilatation. Most patients with AA dilatation have tricuspid aortic valves (TAV). However, previous studies have mainly focused on AA dilation in individuals with bicuspid aortic valves (BAV) using either hemodynamic or circulating biomarkers separately. Purpose To assess the relationship between hemodynamics in the AA and circulating biomarkers in individuals with mild-to-moderate AA dilatation and age-and-sex matched controls with TAV. Methods The study cohort of individuals with mild-to-moderate AA dilatation were identified based on AA diameter on coronary CT angiography in the population-based Swedish CardioPulmonary BioImage Study (SCAPIS) in Linköping. 54 cases with AA diameter &amp;gt;= 40 mm and 50 controls with AA diameter &amp;lt;40 mm (mean age 59, 19% female) underwent 4D Flow cardiovascular magnetic resonance imaging (CMR). The 4D Flow CMR images were processed to compute mean and maximum velocities, wall shear stress (WSS), flow displacement (FD) at peak systole, and oscillatory shear index (OSI) in the AA. Markers of collagen synthesis and degradation; type I collagen α1 chain (COL1α1), matrix metalloproteinase (MMP)-1,-2,-3,-9,-12) and their inhibitors (TIMP-1,-2,-3,-4), were quantified in plasma (n=104). High sensitivity C-reactive protein and interleukin(IL)-6 were used to assess systemic inflammation. Results FD at the location of maximum dilatation, mean FD and mean OSI were higher in cases compared to controls. Mean velocity, mean WSS and maximum WSS were lower in cases compared to controls. None of the circulating biomarkers differed significantly between cases and controls. Interestingly, several circulating biomarkers correlated with hemodynamics markers in the whole cohort. COL1α1, MMP-2 and TIMP-2 correlated inversely with max OSI (r=-0.342, p=0.001; r=-0.277, p=0.006; r=-0.238, p=0.018, respectively) while MMP-3 correlated positively with mean velocity (r=0.274, p=0.006), mean WSS (r=0.270, p=0.007), max WSS (r=0.220, p=0.029), and inversely with FD at the location of maximum dilatation (r=-0.218, p=0.031). TIMP-4 correlated with mean OSI (r=-0.284, p=0.005). Conclusions Several hemodynamic markers obtained with 4D Flow CMR were altered in mild-to-moderate AA dilatation with TAV, while circulating biomarkers did not differ from controls. However, significant correlations were identified between several biomarkers and hemodynamic markers. We therefore speculate that the levels of circulating biomarkers may be altered as the disease progresses. Future studies should examine the implications of these novel findings along the trajectory of AA dilation and its association with complication risk.Methods figureHemodynamics markers table

Evaluation of Citrus junos Essential Oil as a Promising Anti-aging Ingredient: In Vitro and Clinical Studies on Skin Health Improvement

Purpose: This study assessed Citrus junos essential oil (CJEO) as an anti-aging agent for improving skin health.Methods: CJEO was extracted from authenticated C. junos fruit peels, and its chemical composition was analyzed using a gas chromatographymass spectrometry (GC-MS). In vitro experiments were conducted on human epidermal keratinocytes (HEKs) and human dermal fibroblasts (HDFs) to evaluate CJEO’s impact on cell viability, anti-inflammatory activity, collagen synthesis, and collagen degradation. The expression of TNF-α, IL-1β, IL-6, NF-κB, MMP-1, MMP-3, COL1A1, and COL3A1 was quantified using RT-qPCR. A dermal patch test was performed on human participants to assess potential skin irritation, and clinical evaluations were conducted on 20 female participants to analyze CJEO’s effects on skin elasticity.Results: CJEO effectively inhibited nitric oxide production and significantly suppressed the expression of inflammatory markers, including TNF-α, IL-1β, IL-6, and NF-κB, as well as collagen degradation markers MMP-1 and MMP-3. Furthermore, CJEO treatment upregulated the expression of genes associated with collagen synthesis, specifically COL1A1 and COL3A1. Notably, significant improvements in skin elasticity were observed in the 20 female participants. The dermal patch test indicated excellent tolerance of the CJEO emulsion without causing irritation.Conclusions: CJEO exhibits promising potential as a bioactive ingredient in anti-aging cosmeceuticals. Its anti-inflammatory properties, ability to stimulate collagen synthesis, suggest efficacy in reducing skin aging and promoting overall skin health. Additionally, the dermal patch test confirms CJEO’s safety, supporting its suitability for use in cosmetic formulations. These findings endorse CJEO as an effective and safe component in anti-aging skincare products.

Effects of Aging on Collagen in the Skeletal Muscle of Mice.

Aging affects several tissues in the body, including skeletal muscle. Multiple types of collagens are localized in the skeletal muscle and contribute to the maintenance of normal muscle structure and function. Since the effects of aging on muscle fibers vary by muscle fiber type, it is expected that the effects of aging on intramuscular collagen might be influenced by muscle fiber type. In this study, we examined the effect of aging on collagen levels in the soleus (slow-twitch muscle) and gastrocnemius (fast-twitch muscle) muscles of 3-, 10-, 24-, and 28-month-old male C57BL/6J mice using molecular and morphological analysis. It was found that aging increased collagen I, III, and VI gene expression and immunoreactivity in both slow- and fast-twitch muscles and collagen IV expression in slow-twitch muscles. However, collagen IV gene expression and immunoreactivity in fast-twitch muscle were unaffected by aging. In contrast, the expression of the collagen synthesis marker heat shock protein 47 in both slow- and fast-twitch muscles decreased with aging, while the expression of collagen degradation markers increased with aging. Overall, these results suggest that collagen gene expression and immunoreactivity are influenced by muscle fiber type and collagen type and that the balance between collagen synthesis and degradation tends to tilt toward degradation with aging.

10 Extra-label bisphosphonate effects on bone turnover biomarkers in juvenile, exercising horses

Bisphosphonates, such as clodronate disodium (CD), modulate bone metabolism and, though their extra-label use in young horses is common, impacts on skeletal development and longevity are unknown. The objective of the current study was to determine the effects of CD use on systemic biomarkers of bone turnover in juvenile, exercising horses. We hypothesized that bone resorption would decrease, and bone formation would increase as a result of CD administration and repeat treatments would have a greater effect. To test this, 32 juvenile Quarter Horses were used in a 168-d trial. Horses were stratified by age (500 ± 13 d), BW (336 ± 26 kg), sex (n = 16 geldings; n = 16 fillies), and initial bone optical density and randomly allocated to one of 4 treatment groups receiving either 1.8 mg/kg BW CD (OSPHOS®) or isovolumetric saline (placebo). Investigators were blinded to treatments which included a control (CON; n = 8), single-dose CD on d 84 (1X; n = 8), 2-doses CD on d 0 and 84 (2X; n = 8), and 4-doses CD on d 0, 42, 84, and 126 (4X; n = 8). Horses were housed individually in stalls (3.6 × 7.3 m), fed 1% BW/d concentrate, and allowed ad libitum access to Coastal bermudagrass hay and water. Horses exercised 5 d/wk using a free stall exerciser with a phase-based progressive workload; phase I (d 0–84) simulated sales preparation and phase II (d 85–168) mimicked an early training program. Blood was collectedon d 0, 42, 84, 126, and 168, before treatment injections on days of administration. Serum was analyzed for receptor activator of nuclear factor kB ligand (RANKL), tartrate resistant acid phosphatase 5b (TRAP5b), c-terminal crosslinks of type I collagen (CTX-1) and bone-specific alkaline phosphatase (BAP) via commercial ELISA or EIA kits. All data were analyzed using PROC MIXED of SAS with a baseline covariate for BAP and BAP:TRAP5b. No differences were seen in osteoclastic differentiation signal RANKL (P ≥ 0.24). In contrast, a treatment × time interaction was noted for osteoclastic TRAP5b (P = 0.03); specifically, TRAP5b decreased in 4X from d 0 to 126 before returning to baseline at d 168 and decreased in 2X at d 84 compared with baseline, while CON and 1X increased or remained the same over time. Concentrations of CTX-1, a type I collagen degradation marker, increased over time (P < 0.01) in all treatments. Likewise, osteoblastic BAP (P < 0.01) and BAP:TRAP5b (P = 0.04) increased from d 42 to 84 and remained elevated until d 168. These results indicate that multiple doses of CD (2X and 4X) over 168 d reduced activity of osteoclasts despite having no measurable effect on bone formation or type I collagen degradation.

Profile of matrix metalloproteinase activity, markers of collagen and elastin degradation and remodeling during pregnancy, delivery, and puerperium in pelvic organ prolapse 3 months after childbirth

Background: This study aims to assess the condition of pelvic organ prolapse related to changes in matrix metalloproteinase activity, elastin degradation and markers of collagen, and remodeling observed during pregnancy, childbirth, and the puerperal period 3 months postpartum. This study included 39 primigravida women who underwent vaginal delivery with a gestational age &gt;36 weeks. This study conducted laboratory tests using blood and urine samples including procollagen type I N-propeptide (PINP), procollagen type-III N-propeptide (PIIINP), telopeptide carboxyl-terminal collagen type I (ICTP), matrix metalloproteinase-9 (MMP). -9), desmosin, and tropoelastin. The second and third blood samples will be examined 24-48 hours postpartum and 6 weeks postpartum. Method: The Mann-Whitney test and Repeated ANOVA were used to assess the median differences between biomarkers. Results: In the pelvic floor dysfunction and control groups, a significant relationship was found between serum MMP-9 levels 6 weeks postpartum (p=0.025). There were changes in biomarker levels of collagen and elastin during pregnancy, post-partum, and six weeks postpartum. The amount of degradation (MMP-9) seems to be correlated with the event of POP after childbirth. Conclusion: There were changes in the biomarker levels of collagen and elastin from pregnancy, post-partum, and six weeks postpartum. In addition, the difference was significant in MMP-9 level six weeks after postpartum in POP group compare to control.

17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice.

Estrogen signaling is protective against chronic liver diseases, although men and a subset of women are contraindicated for chronic treatment with 17β-estradiol (17β-E2) or combination hormone replacement therapies. We sought to determine if 17α-estradiol (17α-E2), a naturally occurring diastereomer of 17β-E2, could attenuate liver fibrosis. We evaluated the effects of 17α-E2 treatment on collagen synthesis and degradation rates using tracer-based labeling approaches in male mice subjected to carbon tetrachloride (CCl4)-induced liver fibrosis. We also assessed the effects of 17α-E2 on markers of hepatic stellate cell (HSC) activation, collagen cross-linking, collagen degradation, and liver macrophage content and polarity. We found that 17α-E2 significantly reduced collagen synthesis rates and increased collagen degradation rates, which was mirrored by declines in transforming growth factor β1 (TGF-β1) and lysyl oxidase-like 2 (LOXL2) protein content in liver. These improvements were associated with increased matrix metalloproteinase 2 (MMP2) activity and suppressed stearoyl-coenzyme A desaturase 1 (SCD1) protein levels, the latter of which has been linked to the resolution of liver fibrosis. We also found that 17α-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-β1 signaling, and reduced proinflammatory macrophage activation and cytokines expression in the liver. We conclude that 17α-E2 reduces fibrotic burden by suppressing HSC activation and enhancing collagen degradation mechanisms. Future studies will be needed to determine if 17α-E2 acts directly in hepatocytes, HSCs, and/or immune cells to elicit these benefits.

Abstract 12381: Elevated Serum Carboxy-Terminal Telopeptide of Type I Collagen is Associated With Clinical Outcomes in Patients With Stable Angina Pectoris Undergoing Percutaneous Coronary Intervention

Background: Despite high risk of developing cardiovascular events, it was reported to be difficult to predict clinical outcomes in patients with stable angina pectoris (AP). Serum carboxy-terminal telopeptide of type I collagen (I-CTP), a marker of collagen degradation, was reportedly associated with clinical outcomes in patients with acute coronary syndrome. However, clinical usefulness of I-CTP has not yet been elucidated in patients with stable AP. The aim of this study was to examine whether I-CTP can predict clinical outcomes in patients with stable AP. Methods and Results: Serum I-CTP levels were measured in consecutive 360 patients with stable AP undergoing percutaneous coronary intervention. All patients were divided into three groups according to serum I-CTP tertiles: low I-CTP group (≤4.4 ng/ml, n=120), middle I-CTP group (4.5-6.2 ng/ml, n=118), and high I-CTP group (≥6.3 ng/ml, n=122). The high I-CTP group was older and showed higher levels of brain natriuretic peptide (BNP) and lower levels of estimated glomerular filtration rate (eGFR) and left ventricular ejection fraction (LVEF) compared with other groups. During the median follow up period of 1,347 days, there were 68 cardiovascular events including all-cause deaths. Kaplan-Meier analysis showed that the high I-CTP group had the greatest risk for cardiovascular events among 3 groups. Univariate Cox proportional hazard regression analysis showed that age, multivessel disease, BNP, eGFR, LVEF, and I-CTP were significantly associated with cardiovascular events. Multivariate Cox proportional hazard analysis demonstrated that I-CTP was an independent predictor for cardiac events after adjusting for confounding risk factors. Conclusion: I-CTP could be the feasible marker for predicting cardiovascular events in patients with stable AP.

The C-Terminal Cross-linked Telopeptide of Type I Collagen (CTX-I) as a Potential Cardiomyopathy Biomarker in Friedreich Ataxia Patients.

Friedreich's ataxia (FRDA) is the most common inherited recessive ataxia. Cardiomyopathy (CM) with myocardial hypertrophy is the predominant cause of death. The presence of CM is variable and the risk factors for cardiac involvement are not entirely clear. Markers of collagen degradation, such as C-terminal cross-linked telopeptide of type I collagen (CTX-I), seem to be associated with unfavorable cardiovascular outcomes. The aim of our study was to measure serum CTX-I as a marker of cardiac fibrosis in FRDA patients. We measured serum CTX value in twenty-five FRDA patients (mean age, 31.3 ± 14.7years) and nineteen healthy controls (mean age, 34.0 ± 13.5years). Patients underwent echocardiography and SARA scale evaluation. CTX values were significantly higher in the patients than in the control group (31.82 ± 2.27 vs 16.44 ± 1.6μg/L; p = 0.006). CTX-I was inversely correlated with age (R = - 0,535; n = 44; p < 0.001). The regression model identified disease duration and TT3 levels to be independent predictors of CTX-I (model R2 = 0.938; intercept - 64.0, p = 0.071; disease duration coefficient = - 2.34, p = 0.005; TT3 coefficient = 127.17, p = 0.011). CTX-I, a biomarkers of collagen turnover, is elevated in FRDA and should provide complementary information to identify patients with high cardiological risk even if longitudinal studies are needed to define the role of this serologic marker of collagen metabolism in the natural history of cardiomyopathy in FRDA patients.

Abstract P2051: Incomplete Regression And Persistence Of Interstitial Fibrosis Following Removal Of Left Ventricular Pressure Overload

Background: Left ventricular pressure overload (LVPO) can develop from antecedent conditions, like aortic stenosis, and is associated with increased myocardial collagen content that can lead to increases in myocardial stiffness. Alleviation of LVPO in patients undergoing surgical aortic valve replacement (SAVR) resulted in reduced but persistent fibrosis evident in biopsies taken 5-yrs following SAVR. Little is known regarding cellular mechanisms that contribute to ECM turnover following hemodynamic unloading. Objective: Determine the time course of ECM remodeling after alleviation of LVPO. Methods: Transverse aortic constriction (TAC) was used to induce LVPO. Following 4wks of TAC, alleviation of LVPO was performed by removing the TAC band (unTAC). Five time points were assessed: Control no TAC, 4wk TAC, 4wk TAC+2wk unTAC, 4wk TAC+4wk unTAC, and 4wk TAC+6wk unTAC for cardiomyocyte cross-sectional area (CSA), collagen volume fraction (CVF), collagen degradation, and myocardial stiffness. Results: CSA increased by 47% at 4wk TAC vs control. Compared to 4wk TAC, CSA decreased by 20% at 2wk unTAC, but returned to control levels by 6wk unTAC. CVF increased by 204% at 4wk TAC vs control. Although CVF was similar between 4wk TAC and 2wk unTAC, 2wk unTAC demonstrated robust increases in markers of collagen degradation (cathepsin K, pro-matrix metalloproteinase 2 (pro-MMP2), MMP3, and MMP8). CVF significantly decreased at 4wk unTAC compared to 2wk unTAC. However, the markers of collagen degradation were reduced by 4wk- and 6wk unTAC likely contributing to persistent fibrosis. Furthermore, passive stiffness remained elevated at 6wk unTAC. Conclusion: In LVPO hearts, hypertrophy and fibrosis were present. Although cardiomyocyte hypertrophy fully regressed with normalization of hemodynamic load, increased myocardial stiffness and elevated interstitial fibrosis were persistent.

Bone Morphogenetic Protein-9 (BMP9) is Required for Survival and Limits Left Ventricular Matrix Metalloproteinase Activity After Acute Myocardial Infarction

<h3>Purpose</h3> Reorganization of extracellular matrix is a major determinant of short and long term wound healing after acute myocardial infarction (AMI), which includes central roles for matrix metalloproteinases (MMP) and collagen turnover. We recently identified that bone morphogenetic protein (BMP)-9 is a novel endogenous inhibitor of cardiac fibrosis in murine models of pressure overload induced heart failure. We hypothesized that BMP9 regulates MMP activity and is required for survival after AMI. <h3>Methods</h3> WT or BMP9-/- mice were subjected to left anterior descending artery ligation and animals recovered for 2 weeks. Left ventricular (LV) function was assessed using conductance catheter and LV tissue was harvested for molecular analysis in animals surviving to two weeks. To further assess a functional role for BMP9, in vitro studies were performed using human atrial fibroblasts (H-Atr-Fb). <h3>Results</h3> Compared to WT controls BMP9-/- mice had reduced survival (94.4% v 66.7%, p=0.04) and tissue necropsy showed a high rate of cardiac rupture among BMP9-/- mice (BMP9-/- 80%, WT 0%). Ejection fraction and stroke work were reduced and both LV end systolic and diastolic volumes were increased in WT and BMP9-/- mice after AMI. Compared to WT, SMAD3 signaling was increased (p=0.001) and SMAD1 signaling reduced (p=0.03) in BMP9-/- mice after AMI. Compared to WT, BMP9-/- mice had higher LV protein levels of endoglin, Type 1 collagen and periostin. We further observed significantly higher LV MMP9 levels and activity in BMP9-/- compared to WT sham (p=0.003) and WT MI (p=0.02) mice after AMI . Compared to WT, BMP9-/- mice exhibited an increased ratio of circulating markers of collagen degradation and synthesis (ICTP:PINP) after AMI (p=0.02). In H-Atr-Fb, siRNA mediated knockdown of BMP9 increased protein levels of Type I collagen (p<0.05) and MMP9 (p=0.04) and increased MMP9 activity (p=0.003). <h3>Conclusion</h3> We report that BMP9 is necessary for survival after AMI and identify a novel functional role of BMP9 as a negative regulator of MMP9 activity and collagen synthesis in the LV during AMI. These findings suggest that BMP9 may be an important novel target of therapy to improve myocardial recovery and survival after AMI.

Dynamics of fibrotic and vascular endothelial dysfunction markers in elderly hypertensive patients after ischemic stroke receiving beta-blockers

Aim. To compare the effect of beta-blocker therapy (bisoprolol and nebivolol) on the dynamics of fibrotic and vascular endothelial dysfunction markers in elderly hypertensive patients after ischemic stroke (IS).Material and methods. This prospective cohort study included 75 hypertensive patients who were admitted to the hospital due to IS. The mean age of patients was 67±6 years. The average National Institutes of Health Stroke Scale (NIHSS) score was 7±3. The followup period was 6 months. The control group consisted of 20 elderly people with hypertension without prior myocardial infarction. The patients were divided into groups based on received therapy: group 1 (n=38) — bisoprolol; group 2 (n=37) — nebivolol. The level of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) was determined by enzyme-linked immunosorbent assay (ELISAKit, USA). Vascular ultrasound was carried out using a LOGIQP9 (GE) system according to the Celermajer method.Results. After 6-month nebivolol, we revealed a decrease in the level of MMP-9 by 30,2% (p&lt;0,01), TIMP-1 by 15,6% (p&lt;0,05). After 6-month bisoprolol therapy, the level of MMP-9 decreased by 14,5% (p&lt;0,05), while TIMP-1 did not change. Intergroup comparison found that when using nebivolol, there was a higher decrease in the level of MMP-9 by 15,7% (p&lt;0,05), TIMP-1 by 9,7% (p&lt;0,05), MMP-9/TIMP-1 by 7,8% (p&lt;0,05) than with bisoprolol therapy. After 6-month bisoprolol therapy, there was a decrease in the proportion of patients with severe endothelial dysfunction (ED) by 7,9% (p&lt;0,05). Two patients from the nebivolol group moved into mild ED category. The number of patients with moderate ED increased by 19% (p&lt;0,01), while prevalence of severe ED decreased by 24,4% (p&lt;0,01).Conclusion. The results obtained indicate that the beta-blocker nebivolol at an average dose of 8,55+1,75 mg/day significantly reduces the vascular fibrosis, normalizes the ratio of collagen synthesis and degradation markers, improves the vasodilation brachial artery properties in comparison with bisoprolol in elderly hypertensive patients after IS.

Pancreas deficiency modifies bone development in the ovine fetus near term.

Hormones have an important role in the regulation of fetal growth and development, especially in response to nutrient availability in utero. Using micro-CT and an electromagnetic three-point bend test, this study examined the effect of pancreas removal at 0.8 fraction of gestation on the developing bone structure and mechanical strength in fetal sheep. When fetuses were studied at 10 and 25 days after surgery, pancreatectomy caused hypoinsulinaemia, hyperglycaemia and growth retardation which was associated with low plasma concentrations of leptin and a marker of osteoclast activity and collagen degradation. In pancreatectomized fetuses compared to control fetuses, limb lengths were shorter, and trabecular (Tb) bone in the metatarsi showed greater bone volume fraction, Tb thickness, degree of anisotropy and porosity, and lower fractional bone surface area and Tb spacing. Mechanical strength testing showed that pancreas deficiency was associated with increased stiffness and a greater maximal weight load at fracture in a subset of fetuses studied near term. Overall, pancreas deficiency in utero slowed the growth of the fetal skeleton and adapted the developing bone to generate a more compact and connected structure. Maintenance of bone strength in growth-retarded limbs is especially important in a precocial species in preparation for skeletal loading and locomotion at birth.

Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure

Background & AimsAcute-on-chronic liver failure (ACLF) is characterised by organ failure(s), high short-term mortality, and, pathophysiologically, deranged inflammatory responses. The extracellular matrix (ECM) is critically involved in regulating the inflammatory response. This study aimed to determine alterations in biomarkers of ECM turnover in ACLF and their association with inflammation, organ failures, and mortality.MethodsWe studied 283 patients with cirrhosis admitted for acute decompensation (AD) with or without ACLF, 64 patients with stable cirrhosis, and 30 healthy controls. A validation cohort (25 ACLF, 9 healthy controls) was included. Plasma PRO-C3, PRO-C4, PRO-C5, PRO-C6, and PRO-C8 (i.e. collagen type III–VI and VIII formation) and C4M and C6M (i.e. collagen type IV and VI degradation) were measured. Immunohistochemistry of PRO-C6 was performed on liver biopsies (AD [n = 7], ACLF [n = 5]). A competing-risk regression analysis was performed to explore the prognostic value of biomarkers of ECM turnover with 28- and 90-day mortality.ResultsPRO-C3 and PRO-C6 were increased in ACLF compared to AD (p = 0.089 and p <0.001, respectively), whereas collagen degradation markers C4M and C6M were similar. Both PRO-C3 and PRO-C6 were strongly associated with liver function and inflammatory markers. Only PRO-C6 was associated with extrahepatic organ failures and 28- and 90-day mortality (hazard ratio [HR; on log-scale] 6.168, 95% CI 2.366–16.080, p <0.001, and 3.495, 95% CI 1.509–8.093, p = 0.003, respectively). These findings were consistent in the validation cohort. High PRO-C6 expression was observed in liver biopsies of patients with ACLF.ConclusionsThis study shows, for the first time, evidence of severe net interstitial collagen deposition in ACLF and makes the novel observation of the association between PRO-C6 and (extrahepatic) organ failures and mortality. Further studies are needed to define the pathogenic significance of these observations.Lay summaryThis study describes a disrupted turnover of collagen type III and VI in Acute-on-chronic liver failure (ACLF). Plasma biomarkers of these collagens (PRO-C3 and PRO-C6) are associated with the severity of liver dysfunction and inflammation. PRO-C6, also known as the hormone endotrophin, has also been found to be associated with multi-organ failure and prognosis in acute decompensation and ACLF.

Improvement of colonic healing and surgical recovery with perioperative supplementation of inulin and galacto-oligosaccharides

Anastomotic leak (AL) is a major complication in colorectal surgery. Recent evidence suggests that the gut microbiota may affect healing and may cause or prevent AL. Butyrate is a beneficial short-chain fatty acid (SCFA) that is produced as a result of bacterial fermentation of dietary oligosaccharides and has been described as beneficial in the maintenance of colonic health. To assess the impact of oligosaccharides on colonic anastomotic healing in mice, we propose to modulate the microbiota with oligosaccharides to increase butyrate production via enhancement of butyrate-producing bacteria and, consequently, improve anastomotic healing in mice. Animal experiments were conducted in mice that were subjected to diets supplemented with inulin, galacto-oligosaccharides (GOS) or cellulose, as a control, for two weeks before undergoing a surgical colonic anastomosis. Macroscopic and histological assessment of the anastomosis was performed. Extent of epithelial proliferation was assessed by Ki-67 immunohistochemistry. Gelatin zymography was used to evaluate the extent of matrix metalloproteinase (MMP) hydrolytic activity. Inulin and GOS diets were associated with increased butyrate production and better anastomotic healing. Histological analysis revealed an enhanced mucosal continuity, and this was associated with an increased re-epithelialization of the wound as determined by increased epithelial proliferation. Collagen concentration in peri-anastomotic tissue was higher with inulin and GOS diets and MMP activity, a marker of collagen degradation, was lower with both oligosaccharides. Inulin and GOS diets were further associated with lower bacterial translocation. Dietary supplementation with inulin and GOS may improve anastomotic healing and reinforce the gut barrier in mice.