Regulation of matrix turnover: fibroblasts, forces, factors and fibrosis

Abstract

Fibroblasts are multifunctional cells that are responsible for matrix homoeostasis, continuously synthesizing and degrading a diverse group of extracellular molecules and their receptors. Rates of turnover of matrix molecules and the proteases that degrade them are normally under the control of diverse chemical and mechanical cues, with cytokines, growth factors, proteases, lipid mediators and mechanical forces playing roles. The maintenance of this homoeostasis is vital to the preservation of normal tissue function and is clearly lost in chronic diseases of the joints, skin and internal organs where destruction and excessive deposition is seen. Current research is focusing on defining the key pathways of activation either in resident fibroblasts, matrix-producing cells derived from circulating fibrocytes, or from transdifferentiation of resident cells. The common downstream signalling pathways are also being defined, as well as the gene interactions leading to altered cell phenotype. The present article reviews these findings and our current concepts of the key molecular events leading to tissue damage and excessive matrix deposition in tissue fibrosis. These studies are leading to an appreciation of the complexity of events with multiple pathways involved, but, as the facts emerge, we are finding promising new ways to treat fibrosis and halt the inexorable progression that is a feature of so many fibrotic and remodelling disorders.

Increased hyaluronic acid content in idiopathic pulmonary arterial hypertension

“…Later stages of IPAH are dominated by vascular remodelling and characterised by enhanced proliferation and ECM synthesis of PASMC, with increased endothelial cell apoptosis [4,5]. GAGs, major constituents of the lung ECM, have recently been shown to play a significant role in inflammatory and noninflammatory lung diseases, exhibiting spatiotemporally distinct effects on epithelial or mesenchymal cell types [8,9]. GAGs regulate hydration and water homeostasis, maintain cell and tissue structure and function, modulate inflammatory responses and influence tissue repair and remodelling [8,13].…”

“…Altered ECM turnover is a hallmark of several pulmonary diseases, including adult respiratory distress syndrome, asthma, idiopathic pulmonary fibrosis, or chronic obstructive lung disease, which underlines the importance of ECM homeostasis for proper lung function [7][8][9]. In the lung, the ECM is subjected to a daily turnover of ,10% of total ECM, indicating that subtle changes in turnover rates accumulate to produce large changes in total ECM composition with time [10].…”

Airway remodelling: the future

“…However, we should first determine which the best agents are for this purpose and what will be the result in terms of inhibition of the process. Finally, the possibility of modulating fibroblast function may have protective effects on airway diseases additional to those conditions involving the lung parenchyma, such as pulmonary fibrosis [43].…”

Reciprocal Functional Modulation of the Activation of T Lymphocytes and Fibroblasts Derived from Human Solid Tumors

“…4). They represent a major cellular constituent of the tumor microenvironment, particularly in the activated smooth muscle actin-a-containing myofibroblast form (reviewed in Refs.…”