Novel insights into the function and dynamics of extracellular matrix in liver fibrosis

Abstract

Emerging evidence suggests that altered components and posttranslational modifications of proteins in the extracellular matrix (ECM) may both initiate and drive disease progression. The ECM is a complex grid consisting of multiple proteins, most of which play a vital role in containing the essential information needed for maintenance of a sophisticated structure anchoring the cells and sustaining normal function of tissues. Therefore, the matrix itself may be considered as a paracrine/endocrine entity, with more complex functions than previously appreciated. The aims of this review are to 1) explore key structural and functional components of the ECM as exemplified by monogenetic disorders leading to severe pathologies, 2) discuss selected pathological posttranslational modifications of ECM proteins resulting in altered functional (signaling) properties from the original structural proteins, and 3) discuss how these findings support the novel concept that an increasing number of components of the ECM harbor signaling functions that can modulate fibrotic liver disease. The ECM entails functions in addition to anchoring cells and modulating their migratory behavior. Key ECM components and their posttranslational modifications often harbor multiple domains with different signaling potential, in particular when modified during inflammation or wound healing. This signaling by the ECM should be considered a paracrine/endocrine function, as it affects cell phenotype, function, fate, and finally tissue homeostasis. These properties should be exploited to establish novel biochemical markers and antifibrotic treatment strategies for liver fibrosis as well as other fibrotic diseases.

Keywords: collagen; cytokine; endocrine; extracellular fibrogenesis; integrin; laminin; matrix metalloproteinase; posttranslational modification; proteoglycan.

Fig. 1.

Examples of fibroproliferative diseases in different organs. NASH, nonalcoholic steatohepatitis; HCV, hepatitis C virus; HBV, hepatitis B virus; AMD, age-related macular degeneration; IPF, idiopathic pulmonary fibrosis; COPD, chronic obstructive pulmonary disease; ARDS, acute respiratory distress syndrome; FSGS, focal segmental glomerulosclerosis. [From Karsdal et al. (162).]

Fig. 2.

Illustration depicting the changes that occur in the extracellular matrix (ECM) remodeling during the development of fibrosis. The ECM may be divided into the loose basement membrane and the compact interstitial matrix. The basement membrane consists mainly of type IV collagen, laminins, entactin, and proteoglycans and functions to anchor cells and connect to the interstitial ECM. The interstitial matrix has a different composition and consists mainly of fibrillar collagens, numerous noncollagenous glycoproteins, proteoglycans, and elastin. In healthy tissue, ECM remodeling is tightly controlled to ensure homeostasis; the synthesis of ECM proteins by fibroblasts has a relatively slow metabolic turnover, and the proteolytic activity is limited. During fibrogenesis, however, this process is disturbed. As a result of chronic wound healing, immune cells infiltrate the interstitial matrix, which helps drive the profibrotic response. Fibroblasts and fibroblast precursors like hepatic stellate cells differentiate into myofibroblasts, which deposit excessive levels of interstitial collagens. Initially, they may release enhanced levels of ECM-degrading matrix metalloproteinases (MMPs), whereas, at later stages, most MMPs are downregulated. This in turn results in a change in the composition of the ECM, where high levels of ECM degradation products and increased collagen cross-linking can be observed.

Fig. 3.

Binding of certain growth factors and cytokines to the extracellular matrix. The figure highlights prominent interactions. Shown is a selection of relevant ECM binding factors (also discussed in the text) and their association with either heparan sulfate or collagen and their target cells. The liberation of ECM-stored biologically active growth factors and cytokines can either trigger (inflammatory) cells to further degrade ECM or promote excess ECM deposition by (myo)fibroblasts (as is the case with decorin/biglycan-bound transforming growth factor, TGF-β1). EGF, epidermal growth factor; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IL-2, interleukin-2; KGF, keratinocyte growth factor; OsM, oncostatin-M; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor.

Fig. 4.

Schematic representation of the high rate of extracellular matrix remodeling in fibrosis. Healthy ECM consists of a network of fibers organized in a highly ordered fashion. During high matrix turnover, the ECM is degraded, leaving fragments of the ECM in the matrix and releasing other fragments into the circulation, while an accumulation of both new and already existing proteins occur, macroscopically described as fibrosis. ECM remodeling is a delicate equilibrium and a prerequisite for maintenance of a healthy tissue, in which senescent proteins are continuously degraded and replaced by new ones. This delicate balance is disturbed in fibrotic diseases, resulting in an increased ECM turnover (both formation and degradation). Thus a subset of pathological proteases is overexpressed in the affected tissue, resulting in the release of protease-specific fragments of signature proteins of the fibrotic ECM, referred to as protein fingerprints or neoepitopes. These fragments may be used as early diagnostic or prognostic serological markers of tissue degradation and in part formation. PTMs, posttranslational modifications. [From Karsdal et al. (164).]

Fig. 5.

Type VI collagen as autoparacrine and paracrine activator of fibrogenesis. Type VI collagen microfibrils serve as sensor of early tissue injury and ECM destruction, usually initiated by release of ECM-degrading proteases like the MMPs by inflammatory cells. The generated proteolytic fragments activate type VI collagen receptors on (myo)fibroblasts that promote their fibrogenic activation, in part via integrins, focal adhesion kinase, and mitogen-activated kinase (Erk1 and Erk2) activation. There is also coactivation of the mitogenic PDGF-α receptor. The activated myofibroblasts then enhance their deposition of ECM components, including intact type VI collagen, whose ongoing degradation maintains a fibrogenic wound-healing response.