Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was assessed in 145 newly-diagnosed individuals with IPF. Serum levels of collagen synthesis neoepitopes, PRO-C3 and PRO-C6 (collagen type 3 and 6), were elevated in IPF compared with controls at baseline, and progressive disease versus stable disease during follow up, (PRO-C3 p < 0.001; PRO-C6 p = 0.029). Assessment of rate of change in neoepitope levels from baseline to 3 months (defined as ‘slope to month 3’: HIGH slope, slope > 0 vs. LOW slope, slope < =0) demonstrated no relationship with mortality for these markers (PRO-C3 (HR 1.62, p = 0.080); PINP (HR 0.76, p = 0.309); PRO-C6 (HR 1.14, p = 0.628)). As previously reported, rising concentrations of collagen degradation markers C1M, C3M, C6M and CRPM were associated with an increased risk of overall mortality (HR = 1.84, CI 1.03–3.27, p = 0.038, HR = 2.44, CI 1.39–4.31, p = 0.002; HR = 2.19, CI 1.25–3.82, p = 0.006; HR = 2.13 CI 1.21–3.75, p = 0.009 respectively). Elevated levels of PRO-C3 and PRO-C6 associate with IPF disease progression. Collagen synthesis and degradation biomarkers have the potential to enhance clinical trials in IPF and may inform prognostic assessment and therapeutic decision making in the clinic. Electronic supplementary material The online version of this article (10.1186/s12931-019-1118-7) contains supplementary material, which is available to authorized users.

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

“…Fragments from the C-terminal part of the α3 chain have been shown to have signaling effects, including profibrotic features and macrophage chemoattractant properties. One such fragment PRO-COL6/endotrophin is now commonly used as a biomarker in cancer ( 56 ) and fibrotic conditions ( 57 , 58 ) and has been able to distinguish individuals with IPF who have progressive disease from those with more stable disease ( 59 ). We confirmed the presence of high levels of collagen VIα3 in supernatants from freshly isolated Dupuytren’s nodules and in cultured myofibroblasts.…”

Collagen biology and non‐invasive biomarkers of liver fibrosis

“…Type III collagen is found in various tissues and organs, as such PRO‐C3 is not specific to the liver and has been investigated in various aetiologies such as chronic kidney disease, lung fibrosis and cancer . PRO‐C3 is, at the time of writing, only available for investigational use and has yet to be qualified by a regulatory agency.…”

Prolonged Scar-in-a-Jar: an in vitro screening tool for anti-fibrotic therapies using biomarkers of extracellular matrix synthesis

“…Here, a prolonged Scar-in-a-Jar model was used to allow for correct collagen processing, and biochemical markers quantified ECM synthesis for up to 12 days. These markers include PRO-C3 and PRO-C6, biomarkers of type III and VI collagen synthesis, respectively, which have been found to be increased in blood from progressing IPF patients as compared to stable IPF patients in the PRO-FILE (Prospective Observation of Fibrosis in the Lung Clinical Endpoints) study [35]. In addition, serum levels of a marker of myofibroblasts, alpha-smooth muscle actin (α-SMA), has also been shown to be increased in IPF patients compared to healthy controls [36].…”