Chondrocyte Apoptosis in the Pathogenesis of Osteoarthritis.
Hwang Hyun Sook,Kim Hyun Ah
International journal of molecular sciences
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.
Altered Chondrocyte Apoptosis Status in Developmental Hip Dysplasia in Rabbits.
Wei Yi-Shan,Li Dai-He,Liu Wan-Lin,Jiang Dian-Ming
Balkan medical journal
BACKGROUND:Developmental dysplasia of the hip (DDH) is an important factor leading to early adult osteoarthritis. Chondrocyte apoptosis has been proven to be an important factor causing osteoarthritis. AIMS:The current study aims to explore whether a rabbit model of developmental dysplasia of the hip through cast immobilization in the legs results in chondrocyte apoptosis. STUDY DESIGN:Animal experimentation. METHODS:Thirty-two New Zealand white rabbits were divided in three groups with cast plaster-induced dislocation at 2, 4 and 6 weeks. The contralateral hip joint was utilized as a control group. Ten rabbits in each group were sacrificed, and hip specimens were obtained. Bcl-2/Bax, cleaved caspase-3 and cleaved caspase-8 expression were examined by western blot analysis. Chondrocyte apoptosis was analyzed through transmission electron microscopy (TEM) and TUNEL analysis. All experiments were repeated at least three times. RESULTS:In the experimental group, Bcl-2/Bax, cleaved caspase-3 and cleaved caspase-8 expression were significantly altered. The Bcl-2/Bax ratio decreased with time (all p<0.01), whereas levels of cleaved caspase-3 (p<0.01 and p<0.05) and cleaved caspase-8 (all p<0.05) gradually increased. Chondrocyte apoptosis was observed through transmission electron microscopy (TEM) and TUNEL analysis (p<0.05 at 4 weeks and p<0.01 at 6 weeks). CONCLUSION:Prolonged immobilization of rabbit hip caused chondrocyte apoptosis. Reduction of the hip joint may protect chondrocytes from apoptosis, thus preventing secondary osteoarthritis.
Correlation of acetabular chondrocyte apoptosis with caspase-3 and Bcl-2 expression in developmental dislocations of the hip.
Ding L J,Liu Y L,Ma G,Jia Y Q,Wei Y S H,Liu X M
Genetics and molecular research : GMR
This study aimed to determine whether abnormal apoptosis is present in acetabular cartilage in early developmental dislocations of the hip (DDH), and if so, whether it is correlated with the expression of caspase-3 and Bcl-2. DDH was induced in 24 4-week-old New Zealand white rabbits. Acetabular cartilage specimens from the experimental and control groups were stained with hematoxylin and eosin (H&E). Animals from the experimental group developed acetabular dysplasia. Apoptotic chondrocytes were observed by ultrastructural electron microscopy and H&E. TUNEL assays revealed significantly greater acetabular chondrocyte apoptosis in the treated samples as compared to the control. Significantly higher caspase-3 expression and lower Bcl-2 expression were also measured in the DDH group compared with the control. We conclude that excessive apoptosis does occur in acetabular cartilage with DDH, and is positively correlated with high caspase-3 expression as well as low Bcl-2 expression.
Apoptosis and Clearance of Apoptotic Cells.
Annual review of immunology
The human body generates 10-100 billion cells every day, and the same number of cells die to maintain homeostasis in our body. Cells infected by bacteria or viruses also die. The cell death that occurs under physiological conditions mainly proceeds by apoptosis, which is a noninflammatory, or silent, process, while pathogen infection induces necroptosis or pyroptosis, which activates the immune system and causes inflammation. Dead cells generated by apoptosis are quickly engulfed by macrophages for degradation. Caspases are a large family of cysteine proteases that act in cascades. A cascade that leads to caspase 3 activation mediates apoptosis and is responsible for killing cells, recruiting macrophages, and presenting an "eat me" signal(s). When apoptotic cells are not efficiently engulfed by macrophages, they undergo secondary necrosis and release intracellular materials that represent a damage-associated molecular pattern, which may lead to a systemic lupus-like autoimmune disease.
Abdominal paracentesis drainage attenuates severe acute pancreatitis by enhancing cell apoptosis via PI3K/AKT signaling pathway.
Luo Chen,Huang Qilin,Yuan Xiaohui,Yang Yi,Wang Bing,Huang Zhu,Tang Lijun,Sun Hongyu
Apoptosis : an international journal on programmed cell death
Our previous studies have shown that abdominal paracentesis drainage (APD) is a safe and effective strategy for patients with severe acute pancreatitis (SAP). However, the underlying mechanisms behind APD treatment remain poorly understood. Given that apoptosis is a critical pathological response of SAP, we here aim to investigate the effect of APD on cell apoptosis in pancreatic tissues during SAP and to explore its potential molecular mechanism. SAP was induced by 5% sodium-taurocholate retrograde while APD group was inserted a drainage tube into the right lower abdomen of rats immediately after SAP induction. Histopathological staining, serum amylase, endotoxin and inflammatory mediators were measured. Cell apoptosis, apoptosis-related proteins and signaling pathway were also evaluated. Our results demonstrated that APD treatment significantly attenuated pancreatic damage and decreased the serum levels of amylase, endotoxin, TNF-α, IL-1 and IL-6 in rats with SAP. Notably, APD treatment enhanced cell apoptosis and reduced necrosis in pancreatic tissues, as evidenced by Tunnel staining, the increased pro-apoptosis proteins (Cleaved-caspase-3 and bax) and decreased anti-apoptosis protein (Bcl-2). Moreover, the effect of APD on cell apoptosis was further confirmed by the regulatory pathway of PI3K/AKT and NF-kB signaling pathway. These results suggest that APD attenuates the severity of SAP by enhancing cell apoptosis via suppressing PI3K/AKT signaling pathway. Our findings provide new insights for understanding the effectiveness of APD in patients with SAP.
Bax, Bak and beyond - mitochondrial performance in apoptosis.
Peña-Blanco Aida,García-Sáez Ana J
The FEBS journal
Bax and Bak are members of the Bcl-2 family and core regulators of the intrinsic pathway of apoptosis. Upon apoptotic stimuli, they are activated and oligomerize at the mitochondrial outer membrane (MOM) to mediate its permeabilization, which is considered a key step in apoptosis. However, the molecular mechanism underlying Bax and Bak function has remained a key question in the field. Here, we review recent structural and biophysical evidence that has changed our understanding of how Bax and Bak promote MOM permeabilization. We also discuss how the spatial regulation of Bcl-2 family preference for binding partners contributes to regulate Bax and Bak activation. Finally, we consider the contribution of mitochondrial composition, dynamics and interaction with other organelles to apoptosis commitment. A new perspective is emerging, in which the control of apoptosis by Bax and Bak goes beyond them and is highly influenced by additional mitochondrial components.