Moderate activation of Wnt/β‐catenin signaling promotes the survival of rat nucleus pulposus cells via regulating apoptosis, autophagy, and senescence

Intervertebral disc degeneration is a major cause of low back pain. Despite its long history and large socio-economical impact in western societies, the initiation and progress of disc degeneration is not well understood and a generic disease model is lacking. In literature, mechanics and biology have both been implicated as the predominant inductive cause; here we argue that they are interconnected and amplify each other. This view is supported by the growing awareness that cellular physiology is strongly affected by mechanical loading. We propose a vicious circle of mechanical overloading, catabolic cell response, and degeneration of the water-binding extracellular matrix. Rather than simplifying the disease, the model illustrates the complexity of disc degeneration, because all factors are interrelated. It may however solve some of the controversy in the field, because the vicious circle can be entered at any point, eventually leading to the same pathology. The proposed disease model explains the comparable efficacy of very different animal models of disc degeneration, but also helps to consider the consequences of therapeutic interventions, either at the cellular, material or mechanical level.

Intervertebral disc (IVD) degeneration is a complicated process that involves both age-related change and tissue damage caused by multiple stresses. In a degenerative IVD, cellular senescence accumulates and is associated with reduced proliferation, compromised self-repair, increased inflammatory response, and enhanced catabolic metabolism. In this review, we decipher the senescence mechanism of IVD degeneration (IVDD) by interpreting how aging coordinates with age-related, microenvironment-derived stresses in promoting disc cell senescence and accelerating IVDD. After chronic and prolonged replication, cell senescence may occur as a natural part of the disc aging process, but can potentially be accelerated by growth factor deficiency, oxidative accumulation, and inflammatory irritation. While acute disc injury, excessive mechanical overloading, diabetes, and chronic tobacco smoking contribute to the amplification of senescence-inducing stresses, the avascular nature of IVD impairs the immune-clearance of the senescent disc cells, which accumulate in cell clusters, demonstrate inflammatory and catabolic phenotypes, deteriorate disc microenvironment, and accelerate IVDD. Anti-senescence strategies, including telomerase transduction, supply of growth factors, and blocking cell cycle inhibitors, have been shown to be feasible in rescuing disc cells from early senescence, but their efficiency for disc regeneration requires more in vivo validations. Guidelines dedicated to avoiding or alleviating senescence-inducing stresses might decelerate cellular senescence and benefit patients with IVD degenerative diseases.

ABSTRACT 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.