Extracellular matrix organization

ECM composition is highly heterogeneous and dynamic, being constantly remodeled and modulated, largely by matrix metalloproteinases (MMPs) and growth factors that bind to the ECM influencing the synthesis, crosslinking and degradation of ECM components. ECM remodeling is involved in the regulation of cell differentiation processes such as the establishment and maintenance of stem cell niches, branching morphogenesis, angiogenesis, bone remodeling, and wound repair. Redundant mechanisms modulate the expression and function of ECM modifying enzymes. Abnormal ECM dynamics can lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer.

Collagen is the most abundant fibrous protein within the ECM constituting up to 30% of total protein in multicellular animals. Collagen provides tensile strength. It associates with elastic fibres, composed of elastin and fibrillin microfibrils, which give tissues the ability to recover after stretching. Other ECM proteins such as fibronectin, laminins, and matricellular proteins participate as connectors or linking proteins.

Chondroitin sulfate, dermatan sulfate and keratan sulfate proteoglycans are structural components associated with collagen fibrils, serving to tether the fibril to the surrounding matrix. Decorin belongs to the small leucine-rich repeat proteoglycan family (SLRPs) which also includes biglycan, fibromodulin, lumican and asporin. All appear to be involved in collagen fibril formation and matrix assembly.

ECM proteins such as osteonectin (SPARC), osteopontin and thrombospondins -1 and -2, collectively referred to as matricellular proteins (reviewed in Mosher & Adams 2012) appear to modulate cell-matrix interactions. In general they induce de-adhesion, characterized by disruption of focal adhesions and a reorganization of actin stress fibers. Thrombospondin (TS)-1 and -2 bind MMP2. The resulting complex is endocytosed by the low-density lipoprotein receptor-related protein (LRP), clearing MMP2 from the ECM.

Osteopontin (SPP1, bone sialoprotein-1) interacts with collagen and fibronectin. It also contains several cell adhesive domains that interact with integrins and CD44.

Aggrecan is the predominant ECM proteoglycan in cartilage. Its relatives include versican, neurocan and brevican. In articular cartilage the major non-fibrous macromolecules are aggrecan, hyaluronan and hyaluronan and proteoglycan link protein 1 (HAPLN1). The high negative charge density of these molecules leads to the binding of large amounts of water. Hyaluronan is bound by several large proteoglycans proteoglycans belonging to the hyalectan family that form high-molecular weight aggregates, accounting for the turgid nature of cartilage.

The most significant enzymes in ECM remodeling are the Matrix Metalloproteinase (MMP) and A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) families. Other notable ECM degrading enzymes include plasmin and cathepsin G. Many ECM proteinases are initially present as precursors, activated by proteolytic processing. MMP precursors include an amino prodomain which masks the catalytic Zn-binding motif (Page-McCawet al. 2007). This can be removed by other proteinases, often other MMPs. ECM proteinases can be inactivated by degradation, or blocked by inhibitors. Some of these inhibitors, including alpha2-macroglobulin, alpha1-proteinase inhibitor, and alpha1-chymotrypsin can inhibit a large variety of proteinases. The tissue inhibitors of metalloproteinases (TIMPs) are potent MMP inhibitors.