Age-dependent remodeling of connective tissue: role of fibronectin and laminin.

Connective tissues differ from other tissues in their more abundant extracellular matrix (ECM). This matrix is composed of a relatively large number of macromolecules interacting with each other as well as with the cells they are surrounding. Such cells, fibroblasts, chondrocytes and others, secrete the macromolecules of ECM according to a genetically and environmentally regulated "program". It appeared recently that one type of macromolecular interactions is characterized by the selective cleavage of some of the ECM components. Some of these proteolytic cleavage products were shown to possess remarkable biological activities absent from the parent molecules. Such mechanisms were shown to play an important role in aging processes. Also called matricryptins such peptides and their activities are produced from several matrix components. Of special interest are these matricryptins which are derived from fibronectin, laminin and elastin. Their production by proteolytic attack of the original ECM components, followed by their novel biological activities, form in some instances autoamplifying vicious circles. Such "epigenetic", post-translational mechanisms are not coded in the genome, they are neither "accidental", nor "chaotic" but remarkably predictable, the result of the presence in several ECM components of "matricryptic" sites and coregulated synthesis of matrix components carrying such sites and of proteolytic enzymes producing the matricryptins. Some examples will be discussed, derived from the experiments carried out in our laboratory and others over the years, involved in aging and in some of the age-dependent pathologies.