The extracellular matrix (mesoglea) of hydrozoan jellyfish and its ability to support cell adhesion and spreading

The outer mesoglea (extracellular matrix; ECM) of hydrozoan jellyfish was found to contain a species-specific meshwork of striated fibers of different diameters. In the mesoglea, molecules were identified which exhibit several features of well known vertebrate ECM: a laminin-like molecule which appears cross-shaped on electronmicrographs, a fibronectin-like molecule (both detectable by their immunoreactivity at the exumbrella side) and a species-specific collagen consisting of 3 different -chains of which at least 2 can be decorated with con A. The -chains are linked by disulfide bridges. Acetic acid extraction of the mesoglea and subsequent salt precipitation yields fibrils which appear banded in the electron microscope and support species-specific adhesion and spreading of isolated tissue. These precipitated fibrils are mainly composed of the disulfide-linked collagen.     

Brain extracellular matrix

The extracellular matrix of the adult brain tissue has a uniquecomposition. The striking feature of this matrix is the prominenceof lecticans, proteoglycans that contain a lectin domain anda hyaluronic acid-binding domain. Hyaluronic acid and tenascinfamily adhesive/anti-adhesive proteins are also abundant. Matrixproteins common in other tissues are nearly absent in adultbrain. The brain extracellular matrix appears to have trophiceffects on neuronal cells and affect neurite outgrowth. Theunique composition of this matrix may be responsible for theresistance of brain tissue toward invasion by tumors of non-neuronalorigin. extracellular matrix lectican versican review     

The extracellular matrix and synapses

Extracellular matrix (ECM) molecules, derived from both neurons and glial cells, are secreted and accumulate in the extracellular space to regulate various aspects of pre- and postsynaptic differentiation, the maturation of synapses, and their plasticity. The emerging mechanisms comprise interactions of agrin, integrin ligands, and reelin, with their cognate cell-surface receptors being coupled to tyrosine kinase activities. These may induce the clustering of postsynaptic receptors and changes in their composition and function. Furthermore, direct interactions of laminins, neuronal pentraxins, and tenascin-R with voltage-gated Ca²⁺ channels, α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), and γ-aminobutyric acid_B (GABA_B) receptors, respectively, shape the organization and function of different subsets of synapses. Some of these mechanisms significantly contribute to the induction of long-term potentiation in excitatory synapses, either by the regulation of Ca²⁺ entry via N-methyl-D-aspartate receptors or L-type Ca²⁺ channels, or by the control of GABAergic inhibition.A.D. was supported by DFG grants Di 702/4-1,-2 and -3.     

Motif-programmed artificial extracellular matrix

Motif-programming is a method for creating artificial proteins by combining functional peptide motifs in a combinatorial manner. This method is particularly well suited for developing liaison molecules that interface between cells and inorganic materials. Here we describe our creation of artificial proteins through the programming of two motifs, a natural cell attachment motif (RGD) and an artificial Ti-binding motif (minTBP-1). The created proteins were found to reversibly bind Ti and to bind MC3T3-E1 osteoblast-like cells. Moreover, although the interaction with Ti was not covalent, the proteins recapitulated several functions of fibronectin, and thus, could serve as an artificial ECM on Ti materials. Because this motif-programming system could be easily extended to create artificial proteins having other biological functions and material specificities, it should be highly useful for application to tissue engineering and regenerative medicine.     

Assembly of extracellular matrix.

A great challenge in understanding how different extracellular matrices assemble is to sort through the vast number of possible interactions between and among matrix molecules. The most profound insights are likely to come from patients with defined defects of matrix molecules and the use of transgenic mice or other experimental technologies that mimic the complexity of the human system.     

The evolution of extracellular matrix

We present a perspective on the molecular evolution of the extracellular matrix (ECM) in metazoa that draws on research publications and data from sequenced genomes and expressed sequence tag libraries. ECM components do not function in isolation, and the biological ECM system or "adhesome" also depends on posttranslational processing enzymes, cell surface receptors, and extracellular proteases. We focus principally on the adhesome of internal tissues and discuss its origins at the dawn of the metazoa and the expansion of complexity that occurred in the chordate lineage. The analyses demonstrate very high conservation of a core adhesome that apparently evolved in a major wave of innovation in conjunction with the origin of metazoa. Integrin, CD36, and certain domains predate the metazoa, and some ECM-related proteins are identified in choanoflagellates as predicted sequences. Modern deuterostomes and vertebrates have many novelties and elaborations of ECM as a result of domain shuffling, domain innovations and gene family expansions. Knowledge of the evolution of metazoan ECM is important for understanding how it is built as a system, its roles in normal tissues and disease processes, and has relevance for tissue engineering, the development of artificial organs, and the goals of synthetic biology.     

Cysteine cathepsins and extracellular matrix degradation

Background

Cysteine cathepsins are normally found in the lysosomes where they are involved in intracellular protein turnover. Their ability to degrade the components of the extracellular matrix in vitro was first reported more than 25 years ago. However, cathepsins were for a long time not considered to be among the major players in ECM degradation in vivo. During the last decade it has, however, become evident that abundant secretion of cysteine cathepsins into extracellular milieu is accompanying numerous physiological and disease conditions, enabling the cathepsins to degrade extracellular proteins.

Scope of view

In this review we will focus on cysteine cathepsins and their extracellular functions linked with ECM degradation, including regulation of their activity, which is often enhanced by acidification of the extracellular microenvironment, such as found in the bone resorption lacunae or tumor microenvironment. We will further discuss the ECM substrates of cathepsins with a focus on collagen and elastin, including the importance of that for pathologies. Finally, we will overview the current status of cathepsin inhibitors in clinical development for treatment of ECM-linked diseases, in particular osteoporosis.

Major conclusions

Cysteine cathepsins are among the major proteases involved in ECM remodeling, and their role is not limited to degradation only. Deregulation of their activity is linked with numerous ECM-linked diseases and they are now validated targets in a number of them. Cathepsins S and K are the most attractive targets, especially cathepsin K as a major therapeutic target for osteoporosis with drugs targeting it in advanced clinical trials.

General significance

Due to their major role in ECM remodeling cysteine cathepsins have emerged as an important group of therapeutic targets for a number of ECM-related diseases, including, osteoporosis, cancer and cardiovascular diseases. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.     

Proteinases and myocardial extracellular matrix turnover

Extracellular structural remodeling is the compensatory response of the tissue following pathological stage. Myocardial infarction, which leads to adverse remodeling, thinning of the ventricle wall, dilatation and heart failure, is one of the leading causes of death. Remodeling implies an alteration in the extracellular matrix and in the spatial orientation of cells and intracellular components. The extracellular matrix is responsible for cardiac cell alignment and myocardial structural integrity. Substances that break down the extracellular matrix, specialized proteinases as well as inhibitors of proteinases, appear to be normally balanced in maintaining the integrity of the myocardium. Myocardial infarction leads to an imbalance in proteinase/ antiproteinase activities causing alterations in the stability and integrity of the extracellular matrix and adverse tissue remodeling. To explore mechanisms involved in this process and, in particular, to focus on matrix metalloproteinases, their inhibitors, and activators, an understanding of proteinase and antiproteinase is needed. This review represents new and significant information regarding the role of activated matrix proteinases antiproteinases in remodeling. Such information will have a significant impact both on the understanding of the basic cell biology of extracellular matrix turnover, as well as on potential avenues for pharmacological approaches to the treatment of ischemic heart disease and failure.     

Angiotensin II and extracellular matrix homeostasis

As a circulating hormone, endocrine properties of angiotensin (Ang) II are integral to circulatory homeostasis. Produced de novo its autocrine/paracrine properties contribute to biologic responses involving various connective tissues (e.g. extracellular matrix, adipose tissue, bone and its marrow). In this brief review, we develop the concept of extracellular matrix homeostasis, a self regulation of cellular composition and structure, wherein fibroblast-derived AngII regulates elaboration of TGF-beta 1, a fibrogenic cytokine responsible for connective tissue formation at normal and pathologic sites of collagen turnover.