Extracellular matrix molecules: potential targets in pharmacotherapy

Abstract

The extracellular matrix (ECM) consists of numerous macromolecules classified traditionally into collagens, elastin, and microfibrillar proteins, proteoglycans including hyaluronan, and noncollagenous glycoproteins. In addition to being necessary structural components, ECM molecules exhibit important functional roles in the control of key cellular events such as adhesion, migration, proliferation, differentiation, and survival. Any structural inherited or acquired defect and/or metabolic disturbance in the ECM may cause cellular and tissue alterations that can lead to the development or progression of disease. Consequently, ECM molecules are important targets for pharmacotherapy. Specific agents that prevent the excess accumulation of ECM molecules in the vascular system, liver, kidney, skin, and lung; alternatively, agents that inhibit the degradation of the ECM in degenerative diseases such as osteoarthritis would be clinically beneficial. Unfortunately, until recently, the ECM in drug discovery has been largely ignored. However, several of today's drugs that act on various primary targets affect the ECM as a byproduct of the drugs' actions, and this activity may in part be beneficial to the drugs' disease-modifying properties. In the future, agents and compounds targeting directly the ECM will significantly advance the treatment of various human diseases, even those for which efficient therapies are not yet available.

Fig. 1.

Schematic illustration of the ECM and potential targets in pharmacotherapy in the future. 1, targeting the synthesis of the ECM by blocking of specific growth factors such as TGF-β, their receptor molecules, or intracellular signal transduction. 2, controlling of the degradation of ECM by interfering with enzymes involved in ECM remodelling (e.g., MMPs, ADAMTS, cathepsins) and/or their inhibitors. 3, interfering with the ECM signaling pathways (e.g., via integrins) either by blocking the ECM and integrin interactions or subsequent signal transduction. 4, influencing the transcription of specific ECM molecules (e.g., by TFOs). BM, basement membrane; PM, plasma membrane.