Ecm Proteins


 Ecm Proteins Background

The extracellular matrix is a network of molecules that act primarily to support cells and tissue in the body. It is a large component of connective tissue and is divided into the interstitial matrix and basement membrane. The interstitial matrix is made up of various ECM molecules and cells loosely intermingling, whereas the basement membrane is composed of sheets of ECM molecules. The ECM molecules are mostly made up of various proteins, proteoglycans, and hyaluronan. The cells present in the connective tissue secrete ECM molecules and express receptors for attachment to them to help support and allow for growth and proliferation. ECM molecules are also particularly important in development, cell migration, tissue homeostasis, and even tumor invasion.

 

Extracellular matrix proteins in development and disease

The extracellular matrix (ECM) has been shown to be vital in embryonic development and tissue maintenance. In fact, disruption of certain ECM proteins is detrimental to tissue development, and may lead to death. For example, mutations in fibronectin in mice are lethal due to defective development of the neural tube, heart, vasculature network, and extra-embryonic tissues. Osteonectin-null mice have decreased bone remodeling due to low numbers of osteoclast and osteoblast cells, resulting in osteopenia. Periostin-null mice display a subpopulation of MF20/myosin heavy chain positive myocytes and α-smooth muscle actin positive cells within the cardiac valve cushion mesenchyme; a population of cells not seen in normal cushion development. And in vitro addition of purified periostin resulted in reduced expression of myocardial markers as well as an increase in fibroblast markers, indicating that periostin may play a role in encouraging the differentiation of cardiac fibroblasts while preventing the differentiation of valvular progenitor cells into cardiomyocytes and smooth muscle cells.

Clinically, certain diseases or disorders have been associated or caused by a change in the extracellular matrix. For example, Ehlers-Danlos syndromes describe a group of heritable disorders associated with connective tissues. In particular, it is a disruption in collagen proteins and associated remodeling enzymes resulting in fragility of the skin, ligament, blood vessels, and internal organs. Although the general cause is known, the heterogeneity in mutations makes it difficult to know the exact molecular cause and thus difficult to treat. Osteogenesis imperfecta, also known as brittle bone disease, also affects the connective tissue usually due to defects in collagen I production and organization. Marfan’s syndrome is characterized by mutations in fibrillin-1 causing aberrant elastin fiber assembly and resultant defects in the aorta and heart valves. In addition, changes in expression and activity of matrix metalloproteases (MMPs), a family of enzymes that degrade extracellular matrix proteins and thereby facilitate tissue remodeling, have been linked to chronic heart failure (CHF). In particular, an increase of MMP-2, MMP-9, MMP-3, and MMP-13 has been observed in patients with CHF. Although not a direct change of the extracellular matrix proteins of tissues, MMPs will dictate the composition of the ECM microenvironment, which may affect the mechanical properties, cell-cell contact, and intracellular signaling of the cells within the heart.

 

Extracellular matrix proteins and the brain

Integrins are the receptors on cell surfaces that are responsible for recognition of ECM and subsequent cellular response. They are heterodimeric receptors, divided into two functional subunits, α and β. Since ECM molecules have different chemical compositions and interact with each other to form specific structural patterns, integrins respond to their bound ECM’s as a combination of the two subunits based on chemical as well as physical cues.

Integrins are the receptors on cell surfaces that are responsible for recognition of ECM and subsequent cellular response. They are heterodimeric receptors, divided into two functional subunits, α and β. Since ECM molecules have different chemical compositions and interact with each other to form specific structural patterns, integrins respond to their bound ECM’s as a combination of the two subunits based on chemical as well as physical cues. During development, neurons express a large number of integrin receptors to help coordinate successful neural networks, but reduce in number in the adult brain. Developing neurons, therefore, have the ability to grow on multiple different ECM proteins based on their characteristic integrin receptors present. During cell outgrowth, the leading end of the neuron is called the growth cone. It is an amoeboid structure with filopodia outgrowths that respond to extracellular cues in an attempt to reach a target cell to create a synapse. The growth cones of neurons have a large number of integrins that can either cause axon growth or inhibition based on the response to environmental factors. When a growth cone is exposed to a gradient of chemical cues in its environment, the filopodia protrude as a response to polymerization of actin and are exposed to different concentrations of the chemical cues based on location. The filopodia that are exposed to a higher concentration of the chemical cue will have a higher number of integrin binding than those exposed to less concentrated cues. Based on secondary messengers, the growth cone then polarized in response to the chemical cues, leading to the contraction of the cell and the depolymerization at the lagging end of the cell. Therefore, if an ECM protein that attracts neurons is presented to a neuronal growth cone, the integrins will bind to the protein and cause the axon to grow toward the higher concentration of the protein..

During development, neurons express a large number of integrin receptors to help coordinate successful neural networks, but reduce in number in the adult brain. Developing neurons, therefore, have the ability to grow on multiple different ECM proteins based on their characteristic integrin receptors present. During cell outgrowth, the leading end of the neuron is called the growth cone. It is an amoeboid structure with filopodia outgrowths that respond to extracellular cues in an attempt to reach a target cell to create a synapse. The growth cones of neurons have a large number of integrins that can either cause axon growth or inhibition based on the response to environmental factors. When a growth cone is exposed to a gradient of chemical cues in its environment, the filopodia protrude as a response to polymerization of actin and are exposed to different concentrations of the chemical cues based on location. The filopodia that are exposed to a higher concentration of the chemical cue will have a higher number of integrin binding than those exposed to less concentrated cues. Based on secondary messengers, the growth cone then polarized in response to the chemical cues, leading to the contraction of the cell and the depolymerization at the lagging end of the cell. Therefore, if an ECM protein that attracts neurons is presented to a neuronal growth cone, the integrins will bind to the protein and cause the axon to grow toward the higher concentration of the protein. The ECM proteins in the brain are composed mostly of Collagen, Laminin, Fibronectin, Vitronectin, and Tenascin.

ECM proteins present in the brain

Fig. 1 ECM proteins present in the brain with integrin receptors, affected neuronal types, and induced functions.