Extracellular matrix (ECM) turnover and homeostasis is becoming increasingly acknowledged as a pathological factor affected by fibro-inflammatory diseases. This process is involved in multiple different disease indications, including those affecting the liver, kidneys, heart, and lungs. Because of this increasingly clear association to many different pathologies, biomarkers reflecting tissue destruction and fibrosis can be implemented across disease indications to help guide drug development and clinical trial evaluation.
Novel treatments are being investigated for their effect on ECM remodeling, calling in turn for novel biomarkers to reflect this impact; such biomarkers may reveal novel drug targets and help separate pathological pathways. An essential fact of drug development is that biomarkers of ECM remodeling provide tools for evaluating changes to the ground substance in the organs. This is because collagens and other ECM proteins make up the main bulk of organs.
In fact, more than 50 different diseases are associated with changes in the tissues of organs, tissue formation or degradation, leading to tissue changes that affect tissue function. For example, dysregulated tissue homeostasis is a common feature associated with fibro-inflammatory diseases. It is implicated as both a cause and consequence of disease and outcome, is associated with up to 35% of deaths in the western world and is projected to increase. To be truly efficacious, and not just symptomatic, drug developers should also focus on treatments that affect the organs and reverse the organ damage conflicted in the ECM.
Figure 1. Quantifying pathological tissue turnover distinguished from healthy tissue turnover. | During normal tissue homeostasis, there is a balance between tissue formation and degradation, necessary to preserve tissue function. In disease affected tissue the balance is distorted, which can lead to impaired tissue- and organ function. These processes can be quantified by biomarkers reflecting ECM turnover, but advanced assays measuring specific neo-epitopes are needed which accurately quantify both tissue formation and degradation, in order to quantify the balance. |
The process of tissue formation and degradation is constantly ongoing but turns pathological when deposition of newly formed proteins exceeds the degradation or vice versa. These tissue changes can be monitored non-invasively in blood tests, however, it is important to know exactly what the applied biomarkers reflect. Specific neo-epitope generated biomarkers serve as a more accurate measure of ongoing tissue modulation as compared to epitopes that are generically generated, which impacts the information and utility that can be derived thereof (figure 1).
The major constituent of the ECM is collagen. Currently, 28 different types of collagens are known. Each of these collagens give rise to unique epitopes being released during formation and degradation, and these epitopes can be targeted as non-invasive biomarkers to provide insight in tissue turnover, which have the potential of assisting and guiding drug development in several aspects (table 2). These collagens are found in almost all tissues throughout the body but exhibit different expression patterns in diseases.
As a result, the epitopes derived during formation and degradation can provide specific insight in pathological tissue turnover, which can facilitate increased understanding of disease status and progression, and risk of outcome. Therapeutic intervention targeting ECM turnover aiming at restoring tissue homeostasis will have an impact on the serological concentration of ECM epitopes, thus, to develop and market truly efficacious treatments targeting these processes, novel biomarkers are needed.
Table 1. BEST nomenclature applied to ECM biomarkers. Given the ability of ECM biomarkers to accurately reflect ongoing tissue remodeling, they can potentially be used and applied according to several of the BEST classification criteria.
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