Sirtuin 2 expression suppresses oxidative stress and senescence of nucleus pulposus cells through inhibition of the p53/p21 pathway.

Intervertebral disc degeneration (IDD) is a kind of disease associated with nucleus pulposus (NP) cell senescence. Previous studies have shown that the sirtuin family plays an extremely important role in the progress of cell aging. However, whether sirtuin2 (Sirt2) protects against IDD remains unknown. The aim of this study was to determine whether Sirt2 protected NP from degradation in IDD. The expression of Sirt2 in different degree of degenerate disc tissues was determined by reverse transcription-polymerase chain reaction. Interleukin 1 beta (IL-1ß) was used to stimulate the degeneration of NP cells. Subsequently, lentivirus transfection was performed to increase Sirt2 expression in vitro. Meanwhile, the function of Sirt2 overexpression in the progress of NP cell degeneration was evaluated. Our study showed that the expression of Sirt2 markedly decreased in severe degenerated disc tissues. IL-1ß significantly promoted the progress of IDD. Meanwhile, overexpression of Sirt2 could reverse the effects of IL-1ß. The data also revealed that Sirt2 overexpression obviously increased the production of antioxidant SOD1/2 and suppressed oxidative stress in the disc. Moreover, p53 and p21 could be significantly suppressed by Sirt2 overexpression. These results suggested that Sirt2 prevented NP degradation via restraining oxidative stress and cell senescence through inhibition of the p53/p21 pathway. Furthermore, Sirt2 might become a novel target for IDD therapy in the future.

TWEAK/Fn14 signaling: a promising target in intervertebral disc degeneration.

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a potent chemoattractant cytokine with various biological functions, such as stimulation of angiogenesis, induction of proinflammatory cytokines, regulation of cellular proliferation and apoptosis. Therefore, it has also been implicated in several pathological processes, from cancer to inflammatory diseases. Remarkably, TWEAK and its receptors, fibroblast growth factor inducible 14 (Fn14), are also present in intervertebral disc (IVD) tissue, where they play a role in the pathogenesis of IVD degeneration. The interaction of TWEAK with Fn14 is involved in physiological and pathological activities of IVD degeneration patients, which includes apoptosis of endplate chondrocytes, extracellular matrix degradation, reduction in proteoglycan synthesis and so on. The blockade of this interaction results in suppressing over-production of proinflammatory factors and cell death in in vivo or in vitro experiments, suggesting that TWEAK/Fn14 signaling may be therapeutically relevant in IVD degeneration, and the targeting of TWEAK or Fn14 has been proposed as a potential therapeutic approach for autoimmune diseases such as Rheumatoid arthritis (RA). In this article, we discuss the biological features of TWEAK/Fn14 signaling and summarize recent advances in our understanding of the role of TWEAK/Fn14 signaling in the pathogenesis and treatment of IVD degeneration. We think that the blockade of TWEAK/Fn14 signaling may be a promising therapeutic strategy for IVD degeneration in the near future.

Regulatory Tweak/Fn14 signaling pathway as a potent target for controlling bone loss.

Metabolic bone diseases, such as rheumatoid arthritis (RA) and osteoporosis, are characterized as imbalance between bone formation and bone resorption, leading to bone microarchitecture damage and bone mineral density loss. Bone loss is huge threat for older people's health, which imposes a heavy financial burden on patients and their families. However, the effectiveness of bone loss treatment in clinical practice is limited. With the understanding of the molecular and cellular regulators and mediators of bone remodelling, we know that some signaling pathways and inflammatory cytokines play important roles in the development of RA and osteoporosis. The increasing evidence showed that tumor necrosis factor (TNF)-like weak inducer of apoptosis (Tweak)/fibroblast growth factor-inducible 14 (Fn14) signalling controls a variety of cellular activities in biological processes, such as proliferation, differentiation, and apoptosis and has diverse biological functions in pathological mechanisms like inflammation that are associated with the process of bone metabolism. Recent studies suggest that the interactions between Tweak/Fn14 play critical roles in osteoblast and osteoclast differentiation and apoptosis, especially in those rheumatoid arthritis patients. These findings suggest that interventions targeting Tweak/Fn14 signaling pathway to regulate osteoblast-osteoclast coupling according to its biological effects, which results in promoting osteoblast formation and inhibiting osteoclast resorption, may be a promising approach for bone loss prevention and treatment in the near future.