Abstract
Apoptosis is a highly-regulated, active process of cell death involved in development, homeostasis and aging. Dysregulation of apoptosis leads to pathological states, such as cancer, developmental anomalies and degenerative diseases. Osteoarthritis (OA), the most common chronic joint disease in the elderly population, is characterized by progressive destruction of articular cartilage, resulting in significant disability. Because articular cartilage depends solely on its resident cells, the chondrocytes, for the maintenance of extracellular matrix, the compromising of chondrocyte function and survival would lead to the failure of the articular cartilage. The role of subchondral bone in the maintenance of proper cartilage matrix has been suggested as well, and it has been proposed that both articular cartilage and subchondral bone interact with each other in the maintenance of articular integrity and physiology. Some investigators include both articular cartilage and subchondral bone as targets for repairing joint degeneration. In late-stage OA, the cartilage becomes hypocellular, often accompanied by lacunar emptying, which has been considered as evidence that chondrocyte death is a central feature in OA progression. Apoptosis clearly occurs in osteoarthritic cartilage; however, the relative contribution of chondrocyte apoptosis in the pathogenesis of OA is difficult to evaluate, and contradictory reports exist on the rate of apoptotic chondrocytes in osteoarthritic cartilage. It is not clear whether chondrocyte apoptosis is the inducer of cartilage degeneration or a byproduct of cartilage destruction. Chondrocyte death and matrix loss may form a vicious cycle, with the progression of one aggravating the other, and the literature reveals that there is a definite correlation between the degree of cartilage damage and chondrocyte apoptosis. Because current treatments for OA act only on symptoms and do not prevent or cure OA, chondrocyte apoptosis would be a valid target to modulate cartilage degeneration.
Highlights
The regulation of cell death and the subsequent post-mortem change is an essential process of healthy living
Caspase-1 is activated by inflammasomes, which are assembled by the NOD-like receptor (NLR) or pyrin and the HIN domain-containing protein (PYHIN) family member and promotes activation of pro-IL-1β and pro-IL-18 cytokines, which play pro-inflammatory roles [19]
Caspase-independent chondrocyte death was further defined in peroxynitrite-induced death, which involved calcium-dependent cysteine proteases, and in chondrocyte necroptosis induced by the retention of D469del-COMP, a mutated cartilage oligomeric matrix protein gene (COMP) implicated in pseudoachondroplasia [66,131]
Summary
The regulation of cell death and the subsequent post-mortem change is an essential process of healthy living. Programmed cell death, called apoptosis, which was first identified by Kerr [1], is a highly-regulated pathway that involves specific sets of intracellular signals and genes. Disrupted balance of pro- and anti-apoptotic proteins by underexpression and/or overexpression and dysregulated expression of microRNA, which regulates oncogenes or tumor suppressor genes, were observed in cancer cells [6,7,8], resulting in overproliferation and/or dysfunctional removal of cancer cells [9,10]. On the other hand, acquired immune deficiency syndrome is caused by excessive apoptosis of T cells that results from internalization of human immunodeficiency virus into T cells via the CD4 receptor and increased expression of the Fas receptor [12]. Increased levels of caspase-1, -3 and -8 were observed in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model and in PD and Alzheimer’s disease patients’ brains [14]
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