Collagen Biosynthesis, Processing, and Maturation in Lung Ageing

Abstract

In addition to providing a macromolecular scaffold, the extracellular matrix (ECM) is a critical regulator of cell function by virtue of specific physical, biochemical, and mechanical properties. Collagen is the main ECM component and hence plays an essential role in the pathogenesis and progression of chronic lung disease. It is well-established that many chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) primarily manifest in the elderly, suggesting increased susceptibility of the aged lung or accumulated alterations in lung structure over time that favour disease. Here, we review the main steps of collagen biosynthesis, processing, and turnover and summarise what is currently known about alterations upon lung ageing, including changes in collagen composition, modification, and crosslinking. Recent proteomic data on mouse lung ageing indicates that, while the ER-resident machinery of collagen biosynthesis, modification and triple helix formation appears largely unchanged, there are specific changes in levels of type IV and type VI as well as the two fibril-associated collagens with interrupted triple helices (FACIT), namely type XIV and type XVI collagens. In addition, levels of the extracellular collagen crosslinking enzyme lysyl oxidase are decreased, indicating less enzymatically mediated collagen crosslinking upon ageing. The latter contrasts with the ageing-associated increase in collagen crosslinking by advanced glycation endproducts (AGEs), a result of spontaneous reactions of protein amino groups with reactive carbonyls, e.g., from monosaccharides or reactive dicarbonyls like methylglyoxal. Given the slow turnover of extracellular collagen such modifications accumulate even more in ageing tissues. In summary, the collective evidence points mainly toward age-induced alterations in collagen composition and drastic changes in the molecular nature of collagen crosslinks. Future work addressing the consequences of these changes may provide important clues for prevention of lung disease and for lung bioengineering and ultimately pave the way to novel targeted approaches in lung regenerative medicine.

Comparison of the Drug-Induced Efficacies between Omidenepag Isopropyl, an EP2 Agonist and PGF2α toward TGF-β2-Modulated Human Trabecular Meshwork (HTM) Cells

“…In addition, another FP agonist, fluprostenol, was reported to induce a decrease in the expression of COL4 and 6 that was induced by CTGF in cultured TM cells [ 52 ]. In the current study, we also found that TGF-β2 caused a significant up-regulation of the most of ECMs tested and that PGF2α or OMD induced a significant up-regulation of network-forming COL4 [ 53 ] and the down-regulation of beaded-filament-forming COL6 [ 53 ], FN, and αSMA. If 3D spheroid size and stiffness were mainly related with network-forming COL4 and fibril forming COL1, then the PG- or OMD-induced down-regulation of COL6, FN, and αSMA would result in a relative increase in COL1 content, which provides a possible explanation for why PG or OMD caused changes in both the size and stiffness of the 3D spheroids.…”

The Pathogenesis of Cardiac Fibrosis: A Review of Recent Progress

“…CFs and activated CFs are the main cell types responsible for maintaining ECM homeostasis. CFs synthesize collagen as a soluble procollagen with N- and C-terminal propeptide regions that prevent insoluble deposition [ 30 ]. Sequential processing steps are required in the extracellular space for procollagen to become a mature fibril collagen.…”

Peptide location fingerprinting identifies species- and tissue-conserved structural remodelling of proteins as a consequence of ageing and disease

“…In healthy lung however, most ageing studies failed to identify changes to collagen presence (see reviews: [21]) and although the relative proportions of collagen I to III was shown to decrease in aged rats [71], this was not reproduced in mice [72]. In support of this, previous quantification analysis of the dataset analysed here found that the abundances of most lung collagens I and III did not change between aged and young mice [30,73]. Despite this, we identified a segment within Col1a1 displaying a significantly higher peptide yield in young than in aged (Fig.…”

“…Interestingly, this domain is released as a functional fragment (matrikine) during the proteolytic degradation of collagen IV by membrane-anchored (MT) MMPs-14 and -15 [77,78]. Although previous analysis showed that no change in the levels of secreted MMPs [30,73], the MT-MMPs [79] were not identified. It is possible that changes in MMPs 14 and 15 exist because of ageing which may lead to differences in the levels of this fragment, reflected here.…”