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    • The PERF I cohort comprised slightly overweight elderly wome

    2018-11-13

    The PERF I cohort comprised slightly overweight elderly women at risk of developing common western-lifestyle diseases such as type II diabetes, hypertension and hyperlipidemia. These lifestyle diseases affect many tissues and organs resulting in chronic low grade inflammation possibly following fibroproliferative changes to the ECM and thereby collagen degradation. The most prevalent primary causes of death in the PERF cohort were cancer and cardiovascular diseases accounting for 34% and 27% of all deaths, respectively. Similarly, the two largest causes of death for women aged 70–74 in the EU, integrin inhibitors as reported in the European Health Report, are cancer and cardiovascular diseases accounting for 37% and 42% respectively (WHO, 2013). High MMP-mediated type I collagen degradation was associated with both cancer and cardiovascular mortality. At first glance, two markedly different diseases, however with increased tissue turnover being a common denominator of both diseases. The risk of dying from cancer was increased 2.3-fold in the first three years of follow-up and an approximate 1.5-fold increase was observed within the nine year follow-up period in individuals having high MMP-mediated type I collagen degradation. These findings correspond well with the association between ECM remodeling and tumorgenesis (Bonnans et al., 2014; Lu et al., 2012) as ECM remodeling in cancer leads to a dysregulation in tumor growth, inflammation, tissue invasion, and metastasis (Kessenbrock et al., 2010). In addition, risk of dying from cardiovascular diseases was increased 1.8-fold in the first three years of follow-up and an approximate 1.7-fold increase was observed with nine year follow-up period in individuals having high MMP-mediated type I collagen degradation. Atherosclerosis is a typical hallmark of cardiovascular diseases leading to a disturbance of the ECM integrin inhibitors in the artery wall combined with low-grade inflammation. This results in a disrupted structure of the ECM of the artery wall, ultimately leading to cardiovascular disease and fatal events (Hobeika et al., 2007; Raines, 2000; Galis and Khatri, 2002). Other tissue turnover markers have been associated with mortality; albeit not type I collagen degradation by MMPs. P3NP, a formation marker of type III collagen, was associated with all-cause mortality in the Framingham study (Velagaleti et al., 2010). Endostatin, a degradation fragment of type XVIII collagen, was associated with all-cause, cancer and cardiovascular mortality in two independent cohorts from Sweden (Ärnlöv et al., 2013). Degradation and formation are interlinked in the tissue turnover balance, making both processes equally important. Determining the better biomarker is therefore not easy. Formation markers, like P3NP, are generated in all tissues comprising type III collagen. However, when measuring a MMP-mediated degradation product, like C1M, it is a prerequisite that the protease is co-expressed in the affected tissue, making this a specific marker for pathologic tissue turnover. When assessing mortality, MMP-mediated type I collagen degradation may possibly either reflect a consequence or a cause of disease leading to mortality (Karsdal et al., 2010). In order to further answer this question, it would be beneficial to have sequential measurements of C1M which could more closely relate diagnosis of disease rather than early prognosis. In the current study it can only be speculated that some individuals may be predisposed for an increased degradation, potentially making them prone to certain diseases and eventually premature death. Increased serum levels of C1M have shown to be associated with pain and progression of disease in rheumatoid arthritis, and conversely, a decrease by anti-inflammatory modulation (anti-interleukin-6) of more than 35% was associated with protection from disease progression (Siebuhr et al., 2013). This may suggest that attenuation of high remodeling by intervention could be associated with increased life-span. The relation between inflammation and tissue turnover is of particular interest. In autoimmune diseases like rheumatoid arthritis CRP and C1M have been proven to be highly correlated (Siebuhr et al., 2013). In diseases like fibrosis, inflammation may initiate disease, however once present fibrosis can progress without inflammation (Trautwein et al., 2015). The nature and extent of inflammation and ECM remodeling are therefore likely to be very different in different diseases and stages within the same disease. Although this current study identified the prognostic importance of C1M assessment in serum, it remains to be shown whether lowering this marker can result in a reduction of the mortality risk.