Introduction: Catalyzing Matrix Stability

Abstract

An important property of the extracellular matrix (ECM) is its relative insolubility. To survive the unpredictability of the extracellular environment, components of the ECM must be stable to changes in pH, hydration, ionic strength, and red/ox conditions. Biosynthesis and organization of an in­ soluble matrix present complex problems for the cell. Ma­ trix components must be synthesized in soluble form, post­ translationally modified (such as hydroxylation of proline and lysine in collagen), packaged, and transported to specific sites on the cell surface for assembly. During devel­ opment, the cell must adjust both the temporal, qualitative, and quantitative pattern of its synthetic activities to coor­ dinate the amount, type, and spatial organization of matrix components, so as to maintain the phenotypic composition typical of a particular connective tissue. The cell must also remain responsive to physiologic and pathologic stresses that necessitate modification of the matrix. It is now evident that pathways for matrix production form an integrated system regulated at many points by the cell, which can respond to common biologic signals (such as hormones or macro­ molecules from the ECM) thus permitting timing and con­ trol of matrix synthesis by external factors. But regulation of production of ECM components inside the cell is only a part of the story of assembling an ECM. Maturation and insolubilization of an ECM occurs outside the cell, but even here the cell exerts a continued influence over the process. An example is the crosslinking of collagen and elastin. Both proteins leave the cell as soluble monomers that organize into fibers at or near the cell surface. Their in­ solubilization is catalyzed by the extracellular enzyme lysyl oxidase, which oxidatively deaminates the e-amino group of selected lysine and hydroxylysine residues. This appears to be the only enzymatic step involved in crosslinking. Subse­ quent formation of more complex crosslinks (including the tetrafunctional amino acid isomers desmosine and isodes­ mosine) probably occurs as a series of spontaneous conden­ sation reactions. Lysyl oxidase thus occupies a critical posi