Programmed cell death in intervertebral disc degeneration

Intervertebral disc (IVD) degeneration is largely a process of destruction and failure of the extracellular matrix (ECM), and symptomatic IVD degeneration is thought to be one of the leading causes of morbidity or life quality deterioration in the elderly. To date, however, the mechanism of IVD degeneration is still not fully understood. Cellular loss from cell death in the process of IVD degeneration has long been confirmed and considered to contribute to ECM degradation, but the causes and the manners of IVD cell death remain unclear. Programmed cell death (PCD) is executed by an active cellular process and is extensively involved in many physiological and pathological processes, including embryonic development and human degenerative diseases. Thus, the relationship between PCD and IVD degeneration has become a new research focus of interest in recent years. By reviewing the available literature concentrated on PCD in IVD and discussing the methodology of detecting PCD in IVD cells, its inducing factors, the relationship of cell death to ECM degradation, and the potential therapy for IVD degeneration by modulation of PCD, we conclude that IVD cells undergo PCD via different signal transduction pathways in response to different stimuli, that PCD may play a role in the process of IVD degeneration, and that modulation of PCD might be a potential therapeutic strategy for IVD degeneration.     

Role of death receptor,mitochondrial and endoplasmic reticulum pathways in different stages of degenerative human lumbar disc

Intervertebral disc (IVD) cell apoptosis has been suggested to play an important role in promoting the degeneration process. It has been demonstrated that IVD cell apoptosis occurs through either death receptor, mitochondrial or endoplasmic reticulum (ER) pathway. Our study aimed to explore the relationship among these three pathways and grade of IVD degeneration (IVDD). IVDs were collected from patients with lumbar fracture, vertebral tumor, disc herniation or spondylolisthesis. IVDs were distinguished by MRI and histomorphological examination, cell apoptosis was detected by TUNEL staining. Biomarkers of these three apoptosis pathways were detected by RT-PCR and Western blot. Furthermore, the correlation between apoptosis pathways biomarkers and disc pathology were analyzed. Nucleus pulposus cell density decreased with degeneration process, and increased apoptotic ratio. ER pathway was predominant in mild stage of IVDD (GRP78, GADD153 upregulation and caspase-4 activation), death receptor pathway was predominant in mild and moderate stages (Fas, FasL up-regulation and caspase-8 activation) and mitochondrial pathway was predominant in moderate and severe stages (Bcl-2 down-regulation, Bax up-regulation, cytochrome-c accumulation in cytoplasm and caspase-9 activation). There were significant differences in the expressions of Fas, FasL, Bax, GADD153, cytochrome-c and cleaved caspase-8/9/3 between contained and non-contained discs. In conclusion, apoptosis occurs via these three apoptosis pathways together in IVDD. ER pathway plays a more critical role in the mild compared to moderate and severe stages, death receptor pathway in mild and moderate, and mitochondrial pathway in moderate and severe stages of IVDD. Disc cells apoptosis may progress rapidly after herniation, and may depend on the type of herniation.     

Emerging role and therapeutic implication of mTOR signalling in intervertebral disc degeneration

Intervertebral disc degeneration (IDD), an important cause of chronic low back pain (LBP), is considered the pathological basis for various spinal degenerative diseases. A series of factors, including inflammatory response, oxidative stress, autophagy, abnormal mechanical stress, nutritional deficiency, and genetics, lead to reduced extracellular matrix (ECM) synthesis by intervertebral disc (IVD) cells and accelerate IDD progression. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays a vital role in diverse degenerative diseases. Recent studies have shown that mTOR signalling is involved in the regulation of autophagy, oxidative stress, inflammatory responses, ECM homeostasis, cellular senescence, and apoptosis in IVD cells. Accordingly, we reviewed the mechanism of mTOR signalling in the pathogenesis of IDD to provide innovative ideas for future research and IDD treatment.     

Fibroblast growth factor control of cartilage homeostasis

Osteoarthritis (OA) and degenerative disc disease (DDD) are similar diseases involving the breakdown of cartilage tissue, and a better understanding of the underlying biochemical processes involved in cartilage degeneration may allow for the development of novel biologic therapies aimed at slowing the disease process. Three members of the fibroblast growth factor (FGF) family, FGF‐2, FGF‐18, and FGF‐8, have been implicated as contributing factors in cartilage homeostasis. The role of FGF‐2 is controversial in both articular and intervertebral disc (IVD) cartilage as it has been associated with species‐ and age‐dependent anabolic or catabolic events. Recent evidence suggests that FGF‐2 selectively activates FGF receptor 1 (FGFR1) to exert catabolic effects in human articular chondrocytes and IVD tissue via upregulation of matrix‐degrading enzyme production, inhibition of extracellular matrix (ECM) accumulation and proteoglycan synthesis, and clustering of cells characteristic of arthritic states. FGF‐18, on the other hand, most likely exerts anabolic effects in human articular chondrocytes by activating the FGFR3 pathway, inducing ECM formation and chondrogenic cell differentiation, and inhibiting cell proliferation. These changes result in dispersed chondrocytes or disc cells surrounded by abundant matrix. The role of FGF‐8 has recently been identified as a catabolic mediator in rat and rabbit articular cartilage, but its precise biological impact on human adult articular cartilage or IVD tissue remains unknown. The available evidence reveals the promise of FGF‐2/FGFR1 antagonists, FGF‐18/FGFR3 agonists, and FGF‐8 antagonists (i.e., anti‐FGF‐8 antibody) as potential therapies to prevent cartilage degeneration and/or promote cartilage regeneration and repair in the future. J. Cell. Biochem. 114: 735–742, 2013. © 2012 Wiley Periodicals, Inc.     

Disc cell senescence in intervertebral disc degeneration: Causes and molecular pathways

The accumulation of senescent disc cells in degenerative intervertebral disc (IVD) suggests the detrimental roles of cell senescence in the pathogenesis of intervertebral disc degeneration (IDD). Disc cell senescence decreased the number of functional cells in IVD. Moreover, the senescent disc cells were supposed to accelerate the process of IDD via their aberrant paracrine effects by which senescent cells cause the senescence of neighboring cells and enhance the matrix catabolism and inflammation in IVD. Thus, anti-senescence has been proposed as a novel therapeutic target for IDD. However, the development of anti-senescence therapy is based on our understanding of the molecular mechanism of disc cell senescence. In this review, we focused on the molecular mechanism of disc cell senescence, including the causes and various molecular pathways. We found that, during the process of IDD, age-related damages together with degenerative external stimuli activated both p53-p21-Rb and p16-Rb pathways to induce disc cell senescence. Meanwhile, disc cell senescence was regulated by multiple signaling pathways, suggesting the complex regulating network of disc cell senescence. To understand the mechanism of disc cell senescence better contributes to developing the anti-senescence-based therapies for IDD.     

Interaction of pathogenic fungi with host cells: Molecular and cellular approaches

This review provides an overview of several molecular and cellular approaches that are likely to supply insights into the host–fungus interaction. Fungi present intra- and/or extracellular host–parasite interfaces, the parasitism phenomenon being dependent on complementary surface molecules. The entry of the pathogen into the host cell is initiated by the fungus adhering to the cell surface, which generates an uptake signal that may induce its cytoplasmatic internalization. Furthermore, microbial pathogens use a variety of their surface molecules to bind to host extracellular matrix (ECM) components to establish an effective infection. On the other hand, integrins mediate the tight adhesion of cells to the ECM at sites referred to as focal adhesions and also play a role in cell signaling. The phosphorylation process is an important mechanism of cell signaling and regulation; it has been implicated recently in defense strategies against a variety of pathogens that alter host-signaling pathways in order to facilitate their invasion and survival within host cells. The study of signal transduction pathways in virulent fungi is especially important in view of their putative role in the regulation of pathogenicity. This review discusses fungal adherence, changes in cytoskeletal organization and signal transduction in relation to host–fungus interaction.     

Interaction of pathogenic fungi with host cells: Molecular and cellular approaches

This review provides an overview of several molecular and cellular approaches that are likely to supply insights into the host-fungus interaction. Fungi present intra- and/or extracellular host-parasite interfaces, the parasitism phenomenon being dependent on complementary surface molecules. The entry of the pathogen into the host cell is initiated by the fungus adhering to the cell surface, which generates an uptake signal that may induce its cytoplasmatic internalization. Furthermore, microbial pathogens use a variety of their surface molecules to bind to host extracellular matrix (ECM) components to establish an effective infection. On the other hand, integrins mediate the tight adhesion of cells to the ECM at sites referred to as focal adhesions and also play a role in cell signaling. The phosphorylation process is an important mechanism of cell signaling and regulation; it has been implicated recently in defense strategies against a variety of pathogens that alter host-signaling pathways in order to facilitate their invasion and survival within host cells. The study of signal transduction pathways in virulent fungi is especially important in view of their putative role in the regulation of pathogenicity. This review discusses fungal adherence, changes in cytoskeletal organization and signal transduction in relation to host-fungus interaction.     

The influence of serum,glucose and oxygen on intervertebral disc cell growth <Emphasis Type="Italic">in vitro</Emphasis>: implications for degenerative disc disease

Introduction  

The avascular nature of the human intervertebral disc (IVD) is thought to play a major role in disc pathophysiology by limiting nutrient supply to resident IVD cells. In the human IVD, the central IVD cells at maturity are normally chondrocytic in phenotype. However, abnormal cell phenotypes have been associated with degenerative disc diseases, including cell proliferation and cluster formation, cell death, stellate morphologies, and cell senescence. Therefore, we have examined the relative influence of possible blood-borne factors on the growth characteristics of IVD cells in vitro.     

Pathways to caspase activation

Apoptosis or programmed cell death is an active form of cell death which is essential for tissue homeostasis. Many proteins are involved in the molecular signal transduction of apoptosis. The caspase enzymes, a family of specific cysteine proteases, play a central role in cell death machinery. In this review, we mainly discuss the current understanding of several pathways to activate caspases and some key proteins related to these pathways.     

Programmed cell death induced by glutathione depletion in PC 12 cells is blocked by inhibitors of 12 lipoxygenase, but does not appear to be mediated through the formation of 12 HETE derivatives

Lipoxygenase metabolites have been postulated to be involved in the degenerative events provoked by oxidative stress in neuronal and nonneuronal targets, but their roles remain controversial. In the present work, we investigated the putative role of 12 lipoxygenase metabolites in the programmed cell death induced by glutathione depletion in PC 12 cells. Determinations of 12 lipoxygenase expression and activity reveal the presence of the enzyme in PC 12 cells, but the formation of arachidonate metabolites appears rather low and is not influenced by glutathione depletion. In addition, although the death induced by buthionine sulfoximine (BSO) treatment is abolished by known inhibitors of lipoxygenase enzymes, dexamethasone, a potent steroidal inhibitor of both cyclooxygenase and lipoxygenase pathways, fails to protect the cells from BSO-induced degeneration. Finally, incubation of the cells for 24 h in the presence of exogenous 12 HETE did not induce any significant decrease in cell viability. Our results indicate that 12 lipoxygenase is unlikely to play a major role in the process of cell degeneration provoked by glutathione depletion.     

CircSEMA4B targets miR-431 modulating IL-1β-induced degradative changes in nucleus pulposus cells in intervertebral disc degeneration via Wnt pathway

Intervertebral disc (IVD) degeneration (IDD), characterized by elevated levels of proinflammatory mediators, increased Aggrecan and collagen degradation, and increased degradation of extracellular matrix (ECM), has been widely regarded as a significant contributor to low back pain. Genetics are significant factors contribute to IDD. Based on previous data, circular RNA SEMA4B (circSEMA4B) is down-regulated in IDD specimens; herein, we demonstrated circSEMA4B overexpression could attenuate the effect of IL-1β on nucleus pulposus cell (NPC) proliferation, senescence, and ECM and Aggrecan degradation in IDD via Wnt signaling. Moreover, miR-431, a direct target of circSEMA4B, could bind to the 3′UTR of SFRP1 or GSK-3β, two inhibitory regulators of Wnt signaling, to inhibit their expression thus playing a role similar to the activator of Wnt signaling in NPCs. The effect of circSEMA4B knockdown on NPCs was partially reversed by miR-431 inhibition; circSEMA4B serves as a miR-431 sponge to compete with SFRP1 or GSK-3β for miR-431 binding, thus inhibiting IL-1β-induced degenerative process in NPCs through Wnt signaling. Rescuing circSEMA4B expression in NPCs in IDD might present a potential strategy for IDD improvement.     

Pathological mechanism of chondrocytes and the surrounding environment during osteoarthritis of temporomandibular joint

Temporomandibular joint (TMJ) osteoarthritis is a common chronic degenerative disease of the TMJ. In order to explore its aetiology and pathological mechanism, many animal models and cell models have been constructed to simulate the pathological process of TMJ osteoarthritis. The main pathological features of TMJ osteoarthritis include chondrocyte death, extracellular matrix (ECM) degradation and subchondral bone remodelling. Chondrocyte apoptosis accelerates the destruction of cartilage. However, autophagy has a protective effect on condylar chondrocytes. Degradation of ECM not only changes the properties of cartilage but also affects the phenotype of chondrocytes. The loss of subchondral bone in the early stages of TMJ osteoarthritis plays an aetiological role in the onset of osteoarthritis. In recent years, increasing evidence has suggested that chondrocyte hypertrophy and endochondral angiogenesis promote TMJ osteoarthritis. Hypertrophic chondrocytes secrete many factors that promote cartilage degeneration. These chondrocytes can further differentiate into osteoblasts and osteocytes and accelerate cartilage ossification. Intrachondral angiogenesis and neoneurogenesis are considered to be important triggers of arthralgia in TMJ osteoarthritis. Many molecular signalling pathways in endochondral osteogenesis are responsible for TMJ osteoarthritis. These latest discoveries in TMJ osteoarthritis have further enhanced the understanding of this disease and contributed to the development of molecular therapies. This paper summarizes recent cognition on the pathogenesis of TMJ osteoarthritis, focusing on the role of chondrocyte hypertrophy degeneration and cartilage angiogenesis.     

Autophagy in rat annulus fibrosus cells: evidence and possible implications

Introduction  

Programmed cell death of intervertebral disc (IVD) cells plays an important role in IVD degeneration, but the role of autophagy, a closely related cell death event, in IVD cells has not been documented. The current study was designed to investigate the effect of interleukin (IL)-1β on the occurrence of autophagy of rat annulus fibrosus (AF) cells and the interrelationship between autophagy and apoptosis.     

Ser/Thr kinases and polyamines in the regulation of non-canonical functions of elongation factor 1A

The link between eukaryotic translation elongation factor 1A (eEF1A) and signal transduction pathways through the regulatory mechanism of phosphorylation has never been considered. In this review, we focus on the different kinases that recognize the Ser and Thr residues of the eEF1A1 and eEF1A2 isoforms and regulate their involvement in different cellular processes like cell survival and apoptosis. In this context, polyamines seem to play a role in the regulation of the translation elongation process by modulating the Ser/Thr kinases involved in the phosphorylation of translation elongation factors.     

Modeling the role of IGF-1 on extracellular matrix biosynthesis and cellularity in intervertebral disc

The insulin-like growth factor-1 (IGF-1) is a well-known anabolic agent for intervertebral disc (IVD), promoting both proteoglycan (PG) biosynthesis and cell proliferation. Accordingly, it is believed that IGF-1 may play a central role in IVD homeostasis. Furthermore, the exogenous administration of IGF-1 has been proposed as a possible therapeutic strategy for disc degeneration. The objectives of this study were to develop a new computational framework for describing the mechanisms regulating IGF-mediated homeostasis in IVD, and to apply this numerical tool for investigating the effectiveness of exogenous administration of IGF-1 for curing disc degeneration. A diffusive–reactive model was developed for describing competitive binding of IGF-1 to its binding proteins and cell surface receptors, with the latter reaction initiating the intracellular signaling mechanism leading to PG production and cell proliferation. Because PG production increases cell metabolic rate, and cell proliferation increases nutritional demand, nutrients transport and metabolism were also included into the model, and co-regulated, together with IGF-1, IVD cellularity. The sustainability and the effectiveness of IGF-mediated anabolism were investigated for conditions of pathologically insufficient nutrient supply, and for the case of exogenous administration of IGF-1 to degenerated IVD. Results showed that pathological nutrients deprivation, by decreasing cellularity, caused a reduction of PG biosynthesis. Also, exogenous administration of IGF-1 was only beneficial in well-nourished regions of IVD, and exacerbated cell mortality in malnourished regions. These findings remark the central role of nutrition in IVD health, and suggest that adequate nutritional supply is paramount for achieving a successful IGF-based therapy for disc degeneration.     

玉米性别决定的激素调控

玉米(Zea mays)属典型的雌雄异花植物, 单性花的形成经历了复杂的性别决定过程。通过雄穗小花和雌穗下位花的雌蕊原基以及雌穗小花雄蕊原基的选择性败育(或退化), 玉米最终形成正常的雌雄同株单性花。相关突变体的研究揭示, 玉米性别决定涉及选择性细胞死亡、细胞保护及信号转导等复杂的过程。其中, 植物激素信号的调控在玉米性别决定过程中处于核心地位。最近的研究表明, 赤霉素、细胞分裂素和茉莉酸类物质参与调控玉米性别决定过程。该文结合最新研究成果, 综述了植物激素在玉米性别决定中的作用及其调控途径, 同时提出了研究中存在的问题, 并对该领域未来的研究方向进行了展望。     

胶原样分子与肿瘤关系研究进展

细胞外基质不仅维持着体内细胞微环境的稳定,还在细胞的正常生长、增殖以及细胞之间的信号传导中起着重要作用。肿瘤发生时,基质中的分子组分发生了改变,这些改变朝着有利于肿瘤细胞生长侵袭的方向发展。在这个过程中,细胞外基质的主要成分在合成和分解上发生巨大变化,胶原分子便是其中之一,胶原分子作为细胞外基质中的主要成分,对细胞的黏附、运动、迁移等活动起着重要作用。随着研究的深入,发现越来越多的胶原分子参与了肿瘤的发生发展。基质中还存在着一些分子,它们在结构上和胶原蛋白一样含有三螺旋胶原结构域,在肿瘤的发生发展过程中同样发挥着重要作用。本文就包括胶原分子在内的含有胶原结构的分子在肿瘤中的作用做一综述。