Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure

Abstract

Increased attention is paid to the structural components of tissues. These components are mostly collagens and various proteoglycans. Emerging evidence suggests that altered components and noncoded modifications of the matrix may be both initiators and drivers of disease, exemplified by excessive tissue remodeling leading to tissue stiffness, as well as by changes in the signaling potential of both intact matrix and fragments thereof. Although tissue structure until recently was viewed as a simple architecture anchoring cells and proteins, this complex grid may contain essential information enabling the maintenance of the structure and normal functioning of tissue. The aims of this review are to (1) discuss the structural components of the matrix and the relevance of their mutations to the pathology of diseases such as fibrosis and cancer, (2) introduce the possibility that post-translational modifications (PTMs), such as protease cleavage, citrullination, cross-linking, nitrosylation, glycosylation, and isomerization, generated during pathology, may be unique, disease-specific biochemical markers, (3) list and review the range of simple enzyme-linked immunosorbent assays (ELISAs) that have been developed for assessing the extracellular matrix (ECM) and detecting abnormal ECM remodeling, and (4) discuss whether some PTMs are the cause or consequence of disease. New evidence clearly suggests that the ECM at some point in the pathogenesis becomes a driver of disease. These pathological modified ECM proteins may allow insights into complicated pathologies in which the end stage is excessive tissue remodeling, and provide unique and more pathology-specific biochemical markers.

Fig. 1.

The molecular structure of a typical basal lamina. The basal lamina is formed by specific interactions between the proteins type IV collagen, laminin, and entactin plus the proteoglycan Perlecan. Adapted by S.H. Madsen, from Yurchenco and Schittny.

Fig. 2.

Schematic representation of the high extracellular matrix remodeling in fibrosis. All steps involve extracellular matrix (ECM) remodeling that generates unique protein degradation fingerprints. These enzymes degrade the ECM, releasing smaller fragments of protein from the ECM into the circulation. Interestingly, many of the same processes occur in both fibrosis and cancer.

Fig. 3.

Schematic figure of the modifications made to a protein that causes unique subpools to be generated, which each may entail specific pathological or physiological information.

Fig. 4.

Development of an assay to detect a cancer-specific double neoepitope. (A) An enzyme, most likely an MMP, cleaves collagen molecules. This produces a cut in the peptide sequence, exposing an N- and C-terminal-truncated molecule. (B) Lysil oxidase family members are highly upregulated in many cancers. This family of enzymes enzymatically cross-links the lysines in the collagen chains, resulting in stiffened tissue. In the local area of cancer metastasis and growth, these processes are occurring at a more rapid pace than in other parts of the body, resulting in increased expression of a range of collagen, proteases, and other enzymes. (C) The processes of protease generation and lysine cross-linking are combined. (D) Design and generation of a sandwich assay to detect both the lysine cross-link and the protease-generated degradation product. Thus, this type of ELISA contains more information than traditional assays (i.e., both degradation and cross-link information).

Fig. 5.

Relative increases in bone resorption, bone formation, and osteoclastogenesis marker levels as a function of the extent of skeletal metastasis, assessed in 132 patients with breast or prostate cancer. Relative increases are expressed as a percentage of levels in patients with a Soloway score 0.