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| Autophagy: Regulation And Role In Degenerative Diseases (pp.195-210) |
$100.00 |
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Authors: (M. Almonte-Becerril and J. B. Kouri)
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Abstract:
Autophagy is a ubiquitous process that persists at low basal levels in all eukaryotic cells to support homeostasis. According current paradigm, autophagy is an evolutionary conserved and strictly regulated lysosomal pathway to degrade unnecessary or compromised organelles, cytoplasmic and endocytosed materials and even invaded pathogens. Overall autophagy is considered to be adaptive and protective cellular mechanisms. Interestingly, as many other crucial pathways, autophagy plays dual role under normal and pathological conditions. In addition to the well-known role of autophagy in cell survival, autophagy-mediated type II programmed cell death has long been proposed. The autophagic cell death was originally reported in tissues subjected active development and remodeling; that effect seems to be analogous to apoptosis in similar metamorphoses. However, the proposed function of autophagy in cell death is not restricted to the developmental programmed cell death; it also extends to cell death that occurs under various pathological conditions, e.g., immune disorders, infections, and degenerative disorders such as osteoarthritis. It seems that under these circumstances, uncontrolled activation of autophagy capable of massive removal of subcellular structures such as mitochondria can be detrimental to the cell and tissue functions.
Osteoarthritis (OA) is a slowly progressive degenerative disease characterized by gradual loss of articular cartilage, as a consequence of the degradation of extracellular matrix (ECM) components. Presumably, the pathogenesis of this degeneration can be driven by different cellular/molecular mechanisms and the effects of these mechanisms
can be gradually altered upon progress of the disease. Thus, it has been proposed recently that autophagy at a low-level activity can protective against ECM degradation during the early stages of OA. In contrast, in late stages of OA, when a high expression of both autophagic and apoptotic markers can co-exist in the cells constituting both the superficial and middle zones of the cartilage, activation of autophagy is associated with the cell death process termed chondroptosis. Based on these observations, it is possible to conclude, that autophagy plays an important role in both cell survival and cell death mechanism, depending on dominance of the cell signaling pathways. One would expect that a pattern of cellular signals that supports cellular homeostasis under normal conditions would over-activate autophagy under a pathological when cellular signals are over-exaggerated due to failure of homeostasis. This activation of autolysosomal mechanism can exacerbate a slowly-developing degenerative process and lead to cell death.
The objective of this chapter is to discuss a potential role of autophagy in degenerative type of diseases such as osteoarthritis. |
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