Functions of the Extracellular Matrix - Essay Example

? Functions of the Extracellular Matrix: Standard and Disease s April 4, Functions of the Extracellular Matrix Introduction The ECM is the support on which the rest of the mammalian tissues are built. It provides the architecture that guides cell growth and differentiation into various bodily organs and systems, and helps maintain homeostasis (van Horssen et al. 2007). ECM provides the supportive medium necessary for the development of the body's vascular and lymphatic systems, responsible for moving blood and fluids from place to place within the body. It is also what allows chemicals to be passed from the blood to the body cells, providing them with the nutrients they need to survive (Soto-Gutierrez et al. 2010). Without ECM, higher life forms such as mammals, or truly any multi-cellular organism, could not possibly exist. When issues occur with the ECM, though, many problems can then arise. This is seen through the role of the ECM in two pathological states: healing after myocardial infarction, and the degenerative phase of multiple sclerosis. Extracellular Matrix in Healthy Mammals The definition of ECM is extremely broad, now more so than in past years. As it is currently defined in the scientific literature, ECM includes “all secreted molecules that are immobilized outside cells” (van Horssen et al. 2007). Every body tissue has ECM between the cells. In every case, the ECM plays some vital role in the functioning of that tissue. For example, the ECM of the lens of the eyes is responsible for cellular contraction. Cellular contraction, in turn, is what regulates growth rate of the cells on the surface of the eye (Wormstone 2004). The ECM of the periodontal ligament, commonly known as the gum between the jawbone and teeth, is extremely strong. Without it, the teeth would not be able to remain attached to the jawbone, which is vital to the development and maintenance of the bony jaw. This tissue gains such strength mainly through the levels of the collagen type I protein, which are extremely high in the ECM of the periodontal ligament (Bildt et al. 2009). One specialized type of ECM is the the basement membrane. Recently, the role of the basement membrane has been expanded past its previous place as a simple structural feature. This membrane has been shown to be an extremely important regulator of cell behaviour. It helps control tissue compartmentalization and “sends signals to epithelial cells about the external microenvironment”, telling the cells where to grown and how (Kalluri 2003). Balance between creation of new extracellular matrix and its degradation is required for the maintenance of healthy body tissues. This is accomplished through production of matrix metalloproteinases, or MMPs, which are enzymes produced to break down this matrix. The cells which produce these MMPs are known as fibroblasts. Conversely, fibroblasts are also responsible for the synthesis of tissue inhibitors of metalloproteinases. These inhibitors, known as TIMPs, unsurprisingly impede the degradation activity of the MMPs (Bildt et al. 2009). ECM is also responsible for another process in the maintenance of healthy tissue: apoptosis. ECM regulates apoptosis, or programmed cell death, through intracellular signalling (van Horssen et al. 2007). Extracellular matrix could be used as biological scaffolding material for regenerative medicine (Badylak et al. 2009). It can be “decellularized” and the ECM alone used to support new transplanted cells (Soto-Gutierrez et al. 2010). Also relevant to regenerative medicine is the fact that ECM has “constructive remodeling” capability, though the mechanism behind this is not yet fully understood (Badylak et al. 2009) ECM seems like the Holy Grail of biological scaffolding, as it can be constructed and then completely degraded through “bioactive molecules” that are produced naturally within the body (Badylak 2007). Functioning of the ECM in Disease States With the extremely broad and vital roles played by the ECM, it is unsurprisingly that changes in it can be involved in numerous diseases. “Alterations in the localization and composition of the ECM may result in different biological responses and therefore play an important role in disease development and progression” (van Horssen et al. 2007). Since the diseases that involve this sort of ECM alteration are too numerous to count, this paper will focus on two: the role of ECM after myocardial infarction, and the role of ECM in the progression and relapsing nature of multiple sclerosis. While very different diseases, they are similar in the fact that they both relate to the connection of tissue regeneration with ECM. Myocardial Infarction Myocardial infarction is considered an “acute coronary event”, and as such leads to substantial damage to the heart tissue. As part of the healing process, the heart is rebuilt and the damaged tissue repaired or replaced, a process called tissue remodelling; part of this process involves the repaired tissue being “invaded” by large numbers of fibroblast cells, in order to produce the substances necessary for the breakdown and replacement of the damaged ECM. (Riches et al. 2009) If this does not happens properly, future coronary events become more likely. “Whilst the process of postinfarct remodelling is incompletely understood, excessive degradation of extracellular matrix components appears to result in pathological cardiac remodelling, left ventricular dilatation and cardiac failure” (Thompson & Squire 2002). Changes in the heart tissue of this type have also been found to “play a significant role in a number of vascular disorders including aneurysm formation, rupture of atherosclerotic plaques, and development of intimal hyperplasia” (Thompson & Squire 2002). Myocardial infarction is more likely to lead to improper healing of the heart tissue than most types of cell damage. This is due, at least in part, to a reduction of oxygen available to the myocardial tissue as a result of the damage itself. This is what is known as hypoxia. Hypoxia can trigger remodeling and rebuilding of the heart tissue in an erroneous way, and the fibroblast invasion will not occur. Without the new fibroblast cells, the higher levels of MMPs necessary for tissue remodelling cannot be produced, and healing does not occur normally (Riches et al. 2009). Multiple Sclerosis It has long been known that expression of ECM proteins is affected by neurological disorders (van Horssen et al. 2007). The result of diseases of this type is a breakdown in homeostasis in an opposite fashion from myocardial infarction: instead of the ECM not being broken down so it can be repaired, ECM is broken down too quickly, leaving the body with a myriad of problems. Multiple sclerosis, or MS, is one such disease, where an autoimmune attack on the central nervous system results in the degradation of the ECM of the neural tissue (Lawrence Steinman 2001). This ECM degradation leads the lesions of the mylinating tissue of the peripheral nerves that are a hallmark of the disease. This is due to both the actual disappearance of the ECM in those areas, as well as a loss of the ability of the ECM to attach to the other membranes, a property known as “focal adhesion” (Satoh et al. 2009). An obvious result of the lack of ECM is a loss of the proteins created by that material, which has widespread consequences, according to one researcher: “Our ongoing immunohistochemical studies demonstrate enhanced ECM versican, a neurite and axon growth-inhibiting white matter ECM proteoglycan, and dermatan sulfate proteoglycans at the edges of inflammatory MS lesions. This suggests that enhanced proteoglycan deposition in the ECM and axonal growth inhibition may occur early and are involved in expansion of active lesions. Decreased ECM proteoglycans and their phagocytosis by macrophages along with myelin in plaque centers imply that there is "injury" to the ECM itself. These results indicate that white matter ECM proteoglycan alterations are integral to MS pathology at all disease stages and that they contribute to a CNS ECM that is inhospitable to axon regrowth/regeneration.” (Sobel 2001) Other proteins end up being over-produced and leading to similar problems. One such ECM protein is osteopontin, a protein found in elevated levels of those suffering a relapse of the disease. Ostepontin is rather unique in that it is found both in soluble form in the bloodstream and bound to the ECM. (Han & L Steinman 2009). It is produced by macrophages and T cells, which are produced in high numbers by the autoimmune attack. The presence of such high levels down-regulates TH2 cytokines that could otherwise reduce the extent of the MS lesions (Lawrence Steinman 2001). Additionally, osteopontin binds to another protein called integrin, which is related to cell death. This binding stimulates the production of pro-inflammatory cytokines, while simultaneously inhibiting apoptosis of the cells responsible for creating the extraneous osteopontin in the first place (Lawrence Steinman 2009). This positive feedback loop leads sufferers of MS into a relapse state. Conclusions Without ECM , there would be no mammals. It is involved in every tissue in the body, providing the framework for organs and blood vessels and regulating the communication between cells in those structures. When it is damaged due to illness or injury, it usually has a regenerative capability, which is the root of the healing process. However, when this restorative process does not work correctly, there are many consequences to the body. Two conditions that showcase this are the healing process after myocardial infarction and the autoimmune disease multiple sclerosis. Understanding the connection of these disease states with the role of healthy ECM is the first step in understanding how to develop treatments for these disorders, as well as many others. The roles of ECM are so varied that the research possibilities are nearly endless. References Badylak, S.F., 2007. The extracellular matrix as a biologic scaffold material. Biomaterials, 28(25), p.3587-3593. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17524477 [Accessed April 3, 2011]. Badylak, S.F., Freytes, D.O. & Gilbert, T.W., 2009. Extracellular matrix as a biological scaffold material: Structure and function. Acta Biomaterialia, 5(1), p.1-13. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18938117 [Accessed April 3, 2011]. Bildt, M.M. et al., 2009. Matrix metalloproteinase inhibitors reduce collagen gel contraction and ?-smooth muscle actin expression by periodontal ligament cells. Journal of Periodontal Research, 44(2), p.266-274. Available at: http://doi.wiley.com/10.1111/j.1600-0765.2008.01127.x [Accessed April 3, 2011]. Han, M. & Steinman, L, 2009. Systems biology for identification of molecular networks in multiple sclerosis. Multiple Sclerosis, 15(5), p.529 -530. Available at: http://msj.sagepub.com/content/15/5/529.short [Accessed April 4, 2011]. van Horssen, J., Dijkstra, C.D. & de Vries, H.E., 2007. The extracellular matrix in multiple sclerosis pathology. Journal of Neurochemistry, 103(4), p.1293-1301. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17854386 [Accessed April 3, 2011]. Kalluri, R., 2003. Basement membranes: structure, assembly and role in tumour angiogenesis. Nature Reviews. Cancer, 3(6), p.422-433. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12778132 [Accessed April 4, 2011]. Riches, K. et al., 2009. Chronic hypoxia inhibits MMP-2 activation and cellular invasion in human cardiac myofibroblasts. Journal of Molecular and Cellular Cardiology, 47(3), p.391-399. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19523958 [Accessed April 3, 2011]. Satoh, J., Tabunoki, H. & Yamamura, T., 2009. Molecular network of the comprehensive multiple sclerosis brain-lesion proteome. Multiple Sclerosis, 15(5), p.531 -541. Available at: http://msj.sagepub.com/content/15/5/531.abstract [Accessed April 4, 2011]. Sobel, R.A., 2001. The extracellular matrix in multiple sclerosis: an update. Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica ... [et Al, 34(5), p.603-609. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11323746 [Accessed April 3, 2011]. Soto-Gutierrez, A. et al., 2010. Cell Delivery: From Cell Transplantation to Organ Engineering. Cell transplantation, 19(6), p.655-665. Steinman, Lawrence, 2009. A molecular trio in relapse and remission in multiple sclerosis. Nat Rev Immunol, 9(6), p.440-447. Available at: http://dx.doi.org/10.1038/nri2548 [Accessed April 4, 2011]. Steinman, Lawrence, 2001. Multiple sclerosis: a two-stage disease. Nature Immunology, 2, p.762-764. Available at: http://www.mult-sclerosis.org/news/Sep2001/MSTwoStageDisease.html [Accessed April 4, 2011]. Thompson, M.M. & Squire, I.B., 2002. Matrix metalloproteinase-9 expression after myocardial infarction: physiological or pathological? Cardiovascular Research, 54(3), p.495 -498. Available at: http://cardiovascres.oxfordjournals.org/content/54/3/495.short [Accessed April 3, 2011]. Wormstone, I., 2004. Characterisation of TGF-?2 signalling and function in a human lens cell line. Experimental Eye Research, 78(3), p.705-714. Available at: http://linkinghub.elsevier.com/retrieve/pii/S0014483503002434 [Accessed April 3, 2011]. van Horssen, J., Dijkstra, C.D. & de Vries, H.E., 2007. The extracellular matrix in multiple sclerosis pathology. Journal of Neurochemistry, 103(4), p.1293-1301. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17854386 [Accessed April 3, 2011]. Read More