The incidence of low back pain caused by lumbar disc degeneration is high, and it can lead to loss of work ability and impose heavy social and economic burdens. The pathogenesis of low back pain is unclear, and there are no effective treatments. With age, the deposition of advanced glycation end products (AGEs) in intervertebral disc (IVD) gradually increases and is accelerated by diabetes and a high‐AGEs diet, leading to destruction of the annulus fibrosus (AF), nucleus pulposus (NP), and cartilage endplate (CEP) and finally intervertebral disc degeneration (IDD). Reducing the accumulation of AGEs in IVD and blocking the transmission of downstream signals caused by AGEs have a significant effect on alleviating IDD. In this review, we summarize the mechanism by which AGEs induce IDD and potential treatment strategies.

S100A6, also known as calcyclin, is a low-molecular-weight Ca²⁺-binding protein from the S100 family that contains two EF-hands. S100A6 is expressed in a variety of mammalian cells and tissues. It is also expressed in lung, colorectal, pancreatic, and liver cancers, as well as other cancers such as melanoma. S100A6 has many molecular functions related to cell proliferation, the cell cycle, cell differentiation, and the cytoskeleton. It is not only involved in tumor invasion, proliferation, and migration, but also the pathogenesis of other non-neoplastic diseases. In this review, we focus on the molecular mechanisms and potential therapeutic targets of S100A6 in tumors, nervous system diseases, leukemia, endometriosis, cardiovascular disease, osteoarthritis, and other related diseases.

Intervertebral disc (IVD) degeneration (IVDD) is closely linked to degenerative spinal disease, resulting in disability, poor quality of life, and financial burden. Apoptosis of nucleus pulposus (NP) cells (NPCs) is a key pathological basis of IVDD. Periostin (POSTN), an extracellular matrix protein, is expressed in many tissues, whereas its abnormal expression is associated with IVDD. The conventional Wnt/β‐catenin pathway is also involved in IVDD and contributes to NPCs apoptosis. However, research on the mechanisms of POSTN in IVDD is lacking. This study investigated the relationship between POSTN and β‐catenin expression in degenerated IVDs. We detected the expression of POSTN, β‐catenin, and cleaved‐caspase‐3 (C‐caspase3) in degenerated and non‐degenerated IVD tissues of different grades ( n = 8) using RT‐qPCR, immunohistochemical staining, and western blotting analysis. Next, we explored the effects of recombinant periostin (rPOSTN) and isoquercitrin (Iso), an inhibitor of the Wnt/β‐catenin pathway, on NPCs apoptosis. Finally, we inhibited the expression of POSTN in degenerated NPCs in vivo and investigated the anti‐apoptotic effect. The expression of β‐catenin, POSTN, and C‐caspase3 in severe degenerative IVDs was significantly higher than that in mild degenerative IVDs. These findings were confirmed in rat and cell‐based degenerative models. When treated with rPOSTN, the Wnt/β‐catenin pathway activity and cell apoptosis were time‐ and dose‐dependent. However, rPOSTN‐induced NPCs apoptosis decreased after iso‐induced inhibition of the Wnt/β‐catenin pathway. POSTN inhibition reduced apoptosis but was restored by rPOSTN re‐addition. Lastly, POSTN inhibition ameliorated puncture‐induced IVDD in vivo. Overall, our study demonstrated that POSTN promotes NPCs apoptosis and aggravates degeneration by activating the Wnt/β‐catenin pathway.

As a newly discovered mechanosensitive ion channel protein, the piezo1 protein participates in the transmission of mechanical signals on the cell membrane and plays a vital role in mammalian biomechanics. Piezo1 has attracted widespread attention since it was discovered in 2010. In recent years, studies on piezo1 have gradually increased and deepened. In addition to the discovery that piezo1 is expressed in the respiratory, cardiovascular, gastrointestinal, and urinary systems, it is also stably expressed in cells such as mesenchymal stem cells (MSCs), osteoblasts, osteoclasts, chondrocytes, and nucleus pulposus cells that constitute vertebral bodies and intervertebral discs. They can all receive external mechanical stimulation through the piezo1 protein channel to affect cell proliferation, differentiation, migration, and apoptosis to promote the occurrence and development of lumbar degenerative diseases. Through reviewing the relevant literature of piezo1 in the abovementioned cells, this paper discusses the effect of piezo1 protein expression under mechanical stress stimuli on spinal degenerative disease, providing the molecular basis for the pathological mechanism of spinal degenerative disease and also a new basis, ideas, and methods for the prevention and treatment of this degenerative disease.

Intervertebral disc degeneration (IDD) is a prevalent musculoskeletal degenerative disorder worldwide, and ~40% of chronic low back pain cases are associated with IDD. Although the pathogenesis of IDD remains unclear, the reduction in nucleus pulposus cells (NPCs) and degradation of the extracellular matrix (ECM) are critical factors contributing to IDD. Notochordal cells (NCs), derived from the notochord, which rapidly degrades after birth and is eventually replaced by NPCs, play a crucial role in maintaining ECM homeostasis and preventing NPCs apoptosis. Current treatments for IDD only provide symptomatic relief, while lacking the ability to inhibit or reverse its progression. However, NCs and their secretions possess anti‐inflammatory properties and promote NPCs proliferation, leading to ECM formation. Therefore, in recent years, NCs therapy targeting the underlying cause of IDD has emerged as a novel treatment strategy. This article provides a comprehensive review of the latest research progress on NCs for IDD, covering their biological characteristics, specific markers, possible mechanisms involved in IDD and therapeutic effects. It also highlights significant future directions in this field to facilitate further exploration of the pathogenesis of IDD and the development of new therapies based on NCs strategies.

Aims: In this investigation, we administered oxidative stress to nucleus pulposus cells (NPCs), recognized DNA-damage-inducible transcript 4 (DDIT4) as a component in intervertebral disc degeneration (IVDD), and devised a hydrogel capable of conveying small interfering RNA (siRNA) to IVDD.Methods: An in vitro model for oxidative stress-induced injury in NPCs was developed to elucidate the mechanisms underlying the upregulation of DDIT4 expression, activation of the reactive oxygen species (ROS)-thioredoxin-interacting protein (TXNIP)-NLRP3 signalling pathway, and nucleus pulposus pyroptosis. Furthermore, the mechanism of action of small interfering DDIT4 (siDDIT4) on NPCs in vitro was validated. A triplex hydrogel named siDDIT4@G5-P-HA was created by adsorbing siDDIT4 onto fifth-generation polyamidoamine (PAMAM) dendrimer using van der Waals interactions, and then coating it with hyaluronic acid (HA). In addition, we established a rat puncture IVDD model to decipher the hydrogel’s mechanism in IVDD.Results: A correlation between DDIT4 expression levels and disc degeneration was shown with human nucleus pulposus and needle-punctured rat disc specimens. We confirmed that DDIT4 was responsible for activating the ROS-TXNIP-NLRP3 axis during oxidative stress-induced pyroptosis in rat nucleus pulposus in vitro. Mitochondria were damaged during oxidative stress, and DDIT4 contributed to mitochondrial damage and ROS production. In addition, siDDIT4@G5-P-HA hydrogels showed good delivery activity of siDDIT4 to NPCs. In vitro studies illustrated the potential of the siDDIT4@G5-P-HA hydrogel for alleviating IVDD in rats.Conclusion: DDIT4 is a key player in mediating pyroptosis and IVDD in NPCs through the ROS-TXNIP-NLRP3 axis. Additionally, siDDIT4@G5-P-HA hydrogel has been found to relieve IVDD in rats. Our research offers an innovative treatment option for IVDD.Cite this article: Bone Joint Res 2024;13(5):247–260.