Usually the dense extracellular structure in fibrotic tissues is described as extracellular matrix (ECM) or simply as collagen. However, fibrosis is not just fibrosis, which is already exemplified by ...the variant morphological characteristics of fibrosis due to viral versus cholestatic, autoimmune or toxic liver injury, with reticular, chicken wire and bridging fibrosis. Importantly, the overall composition of the ECM, especially the relative amounts of the many types of collagens, which represent the most abundant ECM molecules and which centrally modulate cellular functions and physiological processes, changes dramatically during fibrosis progression.
We hypothesize that there are good and bad collagens in fibrosis and that a change of location alone may change the function from good to bad. Whereas basement membrane collagen type IV anchors epithelial and other cells in a polarized manner, the interstitial fibroblast collagens type I and III do not provide directional information. In addition, feedback loops from biologically active degradation products of some collagens are examples of the importance of having the right collagen at the right place and at the right time controlling cell function, proliferation, matrix production and fate. Examples are the interstitial collagen type VI and basement membrane collagen type XVIII. Their carboxyterminal propeptides serve as an adipose tissue hormone, endotrophin, and as a regulator of angiogenesis, endostatin, respectively.
We provide an overview of the 28 known collagen types and propose that the molecular composition of the ECM in fibrosis needs careful attention to assess its impact on organ function and its potential to progress or reverse. Consequently, to adequately assess fibrosis and to design optimal antifibrotic therapies, we need to dissect the molecular entity of fibrosis for the molecular composition and spatial distribution of collagens and the associated ECM.
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Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to ...SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.
Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of fibrillar collagens in the alveolar space resulting in reduced pulmonary function and a high mortality rate. Biomarkers ...measuring the turnover of type I and III collagen could provide valuable information for prognosis and treatment decisions in IPF.
Serological biomarkers reflecting the formation of type III collagen (PRO-C3) and degradation of type I (C1M) and III collagen (C3M) were evaluated in a real-world cohort of 178 newly diagnosed IPF patients. Blood samples and clinical data were collected at baseline, six, and 12 months. Baseline and longitudinal biomarker levels were related to disease progression of IPF (defined as ≥ 5% decline in forced vital capacity (FVC) and/or ≥ 10% decline in diffusing capacity for carbon monoxide (DLco) and/or all-cause mortality at 12 months). Furthermore, we analysed differences in percentage change of biomarker levels from baseline between patients receiving antifibrotic treatment or not.
Increased baseline levels of type I and III collagen turnover biomarkers were associated with a greater risk of disease progression within 12 months compared to patients with a low baseline type I and III collagen turnover. Patients with progressive disease had higher serum levels of C1M (P = 0.038) and PRO-C3 (P = 0.0022) compared to those with stable disease over one year. There were no differences in biomarker levels between patients receiving pirfenidone, nintedanib, or no antifibrotics.
Baseline levels of type I and III collagen turnover were associated with disease progression within 12 months in a real-world cohort of IPF patients. Longitudinal biomarker levels of type I and III collagen turnover were related to progressive disease. Moreover, antifibrotic therapy did not affect type I and III collagen turnover biomarkers in these patients. PRO-C3 and C1M may be potential biomarkers for a progressive disease behavior in IPF.
During cancer progression, the homeostasis of the extracellular matrix becomes imbalanced with an excessive collagen remodeling by matrix metalloproteinases. As a consequence, small protein fragments ...of degraded collagens are released into the circulation. We have investigated the potential of protein fragments of collagen type I, III and IV as novel biomarkers for colorectal cancer. Specific fragments of degraded type I, III and IV collagen (C1M, C3M, C4M) and type III collagen formation (Pro-C3) were assessed in serum from colorectal cancer patients, subjects with adenomas and matched healthy controls using well-characterized and validated ELISAs. Serum levels of the biomarkers were significantly elevated in colorectal cancer patients compared to subjects with adenomas (C1M, Pro-C3, C3M) and controls (C1M, Pro-C3). When patients were stratified according to their tumour stage, all four biomarkers were able to differentiate stage IV metastatic patients from all other stages. Combination of all markers with age and gender in a logistic regression model discriminated between metastatic and non-metastatic patients with an AUROC of 0.80. The data suggest that the levels of these collagen remodeling biomarkers may be a measure of tumour activity and invasiveness and may provide new clinical tools for monitoring of patients with advanced stage colorectal cancer.
Collagen characteristics contribute to bone biomechanical properties. Yet, few studies have analyzed the independent contributions of bone mineral density (BMD) and post-translational modifications ...of type I collagen to whole bone strength. Thus, the aim of this study was to determine the relative contributions of BMD and both enzymatic and non-enzymatic collagen crosslink concentration to the biomechanical properties of human vertebrae. Nineteen L3 vertebrae were collected after necropsy (age 26–93; 10 males, 9 females). BMD of the vertebral body was measured by DXA, and the vertebrae were compressed to failure to assess the stiffness, failure load and work to fracture. After mechanical testing, the concentration of both enzymatic crosslinks pyridinoline (PYD), and deoxypyridinoline (DPD) as well as, and the non-enzymatic crosslinks pentosidine (PEN) were analyzed in trabecular and cortical bone by reversed-phase HPLC. The extent of aspartic acid isomerization of type I collagen C telopeptide (CTX) was evaluated by ELISA of native (α CTX) and isomerized (β CTX) forms. BMD was significantly positively related with stiffness (R2 = 0.74; P < 0.0001), failure load (R2 = 0.69; P < 0.0001) and work to fracture (R2 = 0.44; P = 0.002). Bivariate regression analysis showed no association between collagen traits and biomechanical properties. However, in a multiple regression model, BMD and trabecular PEN were both significantly associated with failure load and work to fracture (multiple R2 = 0.83, P = 0.001 and R2 = 0.67, P = 0.001, respectively). Similarly, BMD and trabecular α/β CTX ratio were both associated with stiffness (multiple R2 = 0.83, P = 0.015). These findings indicate that post-translational modifications of type I collagen have an impact on skeletal fragility.
Summary Objective Osteoarthritis (OA) is the most common form of arthritic disease, and it is a major cause of disability and impaired quality of life in the elderly. OA is a complex disease of the ...entire joint, including bone and cartilage, thereby presenting alternative approaches for treatment. This review summarizes emerging observations from cell biology to preliminary clinical trials, describing interactions between the bone and cartilage components. We speculate whether a treatment for OA would be possible without targeting the bone compartment? Methods Peer-reviewed articles found using pre-defined search criteria and published in the PubMed database until June 2007 are summarized. In addition, abstracts from the OsteoArthritis Research Society International (OARSI) conferences in the time period 2000–2007 were included. Results Bone and cartilage health seem to be tightly associated. Ample evidence is found for bone changes during progression of OA, including, but not limited to, increased turnover in the subchondral bone, thinning of the trabecular structure, osteophytes, bone marrow lesions and sclerosis of the subchondral plate. In addition, a range of investigations has described secondary positive effects on cartilage health when bone resorption was suppressed, or deterioration of the cartilage when resorption is increased. Conclusion An optimal treatment for OA might include targeting both the bone and cartilage compartments. Hence, as several cell systems are to be targeted in a safe manner, limited options seem possible.
Summary
Background
The hepatic venous pressure gradient (HVPG) is an invasive, but important diagnostic and prognostic marker in cirrhosis with portal hypertension (PHT). During cirrhosis, ...remodelling of fibrotic tissue by matrix metalloproteinases (MMPs) is a permanent process generating small fragments of degraded extracellular matrix (ECM) proteins known as neoepitopes, which are then released into the circulation.
Aim
To investigate their potential as plasma markers for detection of PHT.
Methods
Ninety‐four patients with alcoholic cirrhosis and 20 liver‐healthy controls were included. Clinical and laboratory data of the patients were collected. All patients received HVPG measurement with blood sampling. In these samples, the following degradation or formation markers were measured: C1M (type I‐collagen), C3M and PRO‐C3 (type III collagen), C4M and P4NP 7S (type IV collagen), C5M (type V collagen), C6M (type VI collagen), BGM (biglycan), ELM (elastin), CRPM (CRP).
Results
All ECM markers except for CRPM correlated significantly with HVPG. Interestingly, C4M, C5M and ELM levels were significantly higher in patients with HVPG >10 mmHg. Multiple regression analysis identified PRO‐C3, C6M and ELM as significant determinants, while the models A and B including PRO‐C3, ELM, C6M and model for end‐stage liver disease (MELD) provided better description of PHT (r = 0.75, P < 0.0001). The models provided odds ratios of >100 for having clinical significant PHT.
Conclusions
These novel non‐invasive extracellular matrix markers reflect the degree of liver dysfunction. The different degrees of portal hypertension correlated with these circulating neoepitopes. Using a single blood sample, these neoepitopes in combination with MELD detect the level of portal hypertension.
Summary
Changes in organic matrix may contribute to the anti-fracture efficacy of anti-remodeling agents. Following one year of treatment in beagle dogs, bisphosphonates alter the organic matrix of ...vertebral trabecular bone, while raloxifene had no effect. These results show that pharmacological suppression of turnover alters the organic matrix component of bone.
Introduction
The collagen matrix contributes significantly to a bone’s fracture resistance yet the effects of anti-remodeling agents on collagen properties are unclear. The goal of this study was to assess changes in collagen cross-linking and isomerization following anti-remodeling treatment.
Methods
Skeletally mature female beagles were treated for one year with oral doses of vehicle (VEH), risedronate (RIS; 3 doses), alendronate (ALN; 3 doses), or raloxifene (RAL; 2 doses). The middle dose of RIS and ALN and the lower dose of RAL approximate doses used for treatment of post menopausal osteoporosis. Vertebral trabecular bone matrix was assessed for collagen isomerization (ratio of α/β C-telopeptide CTX), enzymatic (pyridinoline PYD and deoxypyridinoline DPD), and non-enzymatic (pentosidine PEN) cross-links.
Results
All doses of both RIS and ALN increased PEN (+34–58%) and the ratio of PYD/DPD (+14–26%), and decreased the ratio of α/β CTX (−29–56%) compared to VEH. RAL did not alter any collagen parameters. Bone turnover rate was significantly correlated to PEN (R = −0.664), α/β CTX (R = 0.586), and PYD/DPD (R = −0.470).
Conclusions
Bisphosphonate treatment significantly alters properties of bone collagen suggesting a contribution of the organic matrix to the anti-fracture efficacy of this drug class.
Lymphangioleiomyomatosis (LAM) is a rare, female-specific cystic lung disease in which destruction of the lung parenchyma is driven by lesions containing TSC2-/- LAM cells and recruited stromal LAM ...associated fibroblasts (LAFs). LAM patients can be treated with rapamycin to stabilise lung function, but some patients continue to decline, and additional therapies are needed for these patients. We hypothesised that extracellular matrix (ECM) deposited by LAFs within lesions could affect LAM cell behaviour and promote disease progression. We aimed to quantify ECM deposition in LAM, investigate its association with disease severity and study the effect of LAF deposited matrix on LAM cell behaviour in vitro. MethodsCollagen neoepitopes were measured in sera from 96 LAM patients and 22 controls using Nordic Bioscience assays. Collagen deposition in paraffin sections of LAM lung tissue was assayed by picrosirius red (PSR) staining and immunohistochemistry from 19 lung samples with linked clinical data. In vitro assays were performed on TSC2-/- cells grown on cell-free LAF-derived ECM.ResultsSerum markers of collagen, but not elastin turnover tended to be greater in women with LAM than controls (C6M, p=0.057). Quantification of PSR staining revealed trends toward ECM accumulation with increasing disease duration (r=0.62, p=0.060) and reducing DLCO (r=-0.55, p=0.057). LAF-derived ECM increased proliferation (p<0.0001) and reduced the anti-proliferative effect of rapamycin in TSC2-/- cells (p=0.0004) in vitro.ConclusionCollagen deposition can be observed in LAM lesions. LAF-derived ECM enhances TSC2-/- cell proliferation in vitro and may contribute to disease progression by providing a pro-proliferative microenvironment for LAM cells in vivo. This may reduce response to rapamycin in some patients. These data support the investigation of anti-fibrotic therapies for LAM patients who respond poorly to rapamycin.
Summary
Background
Nearly 45% of all deaths are associated with chronic fibroproliferative diseases, of which the primary characteristic is altered remodelling of the extracellular matrix. A major ...difficulty in developing anti‐fibrotic therapies is the lack of accurate and established techniques to estimate dynamics of fibrosis, regression or progression, in response to therapy.
Aim
One of the most pressing needs in modern clinical chemistry for fibroproliferative disorders is the development of biomarkers for early diagnosis, prognosis, and early efficacy for the benefit of patients and to facilitate improved drug development. The aim of this article was to review the serological biomarkers that may assist in early diagnosis of patients, separate fast from slow‐ or nonprogressors, and possibly assist in drug development for fibroproliferative diseases, exemplified by liver fibrosis. The lack of success of biochemical markers and the possible reasons for this is discussed in the context of other fields with biomarker success.
Method
This is a personal opinion review article.
Results
Biochemical markers, originating from the fibrotic structure, may have increased specificity and sensitivity for disease. Assessment of the tissue turnover balance by measurement of tissue formation and tissue degradation separately by novel technologies may provide value.
Conclusions
Novel technologies focused on the protein fingerprint in addition to biomarker classification, may increase the quality of biomarker development and provide the much needed biomarkers to further the fibroproliferative field. This is in direct alignment with the Food and Drug Administration and European Medicinal Agencies initiatives of personal health care.
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