Intervertebral disc (IVD) degeneration contributes largely to pathoanatomical and degenerative changes of spinal structure that increase the risk of low back pain. Apoptosis in nucleus pulposus (NP) can aggravate IVD degeneration, and increasing studies have shown that interventions targeting NP cell apoptosis can ameliorate IVD degeneration, exhibiting their potential for use as therapeutic strategies. Recent data have shown that advanced glycation end products (AGEs) accumulate in NP tissues in parallel with the progression of IVD degeneration and form a microenvironment of oxidative stress. This study examined whether AGEs accumulation aggravates NP cell apoptosis and IVD degeneration, and explored the mechanisms underlying these effects. We observed that the viability and proliferation of human NP cells were significantly suppressed by AGEs treatment, mainly due to apoptosis. Furthermore, activation of the mitochondrial apoptosis pathway was detected after AGEs treatment. In addition, the molecular data showed that AGEs could significantly aggravate the generation of mitochondrial reactive oxygen species and prolonged activation of the mitochondrial permeability transition pore, as well as the increased level of Bax protein and decreased level of Bcl-2 protein in mitochondria. These effects could be reduced by antioxidant (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (MitoTEMPO) and Visomitin (SKQ1). Importantly, we identified that impairment of Sirtuin3 (SIRT3) function and the mitochondrial antioxidant network were vital mechanisms in AGEs-induced oxidative stress and secondary human NP cell apoptosis. Finally, based on findings that nicotinamide mononucleotide (NMN) could restore SIRT3 function and rescue human NP cell apoptosis through adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-γ coactivator 1α (AMPK-PGC-1α) pathway in vitro, we confirmed its protective effect on AGEs-induced IVD degeneration in vivo. In conclusion, our data demonstrate that SIRT3 protects against AGEs-induced human NP cell apoptosis and IVD degeneration. Targeting SIRT3 to improve mitochondrial redox homeostasis may represent a potential therapeutic strategy for attenuating AGEs-associated IVD degeneration.

Osteoporosis can be caused by a multitude of factors and is defined by a decrease in bone density and mass caused by the destruction of bone microstructure, resulting in increased bone brittleness. Thus, it is a systemic bone disease in which patients are prone to fracture. The role of ferroptosis in the pathogenesis of osteoporosis has become a topic of growing interest. In this review, we discuss the cell morphology, basic mechanisms of ferroptosis, the relationship between ferroptosis and osteoclasts and osteoblasts, as well as the relationship between ferroptosis and diabetic osteoporosis, steroid‐induced osteoporosis, and postmenopausal osteoporosis. Emerging biomedical research has provided new insights into the roles of ferroptosis and osteoporosis, such as in cellular function, signaling pathways, drug inhibition, and gene silencing. The pathophysiology and mechanism of ferroptosis and osteoporosis need to be further studied and elucidated to broaden our understanding of iron metabolism and immune regulation. Studies using animal models of osteoporosis in vivo and cell models in vitro will help clarify the relationship between ferroptosis and osteoporosis and provide research ideas for the elucidation of new mechanisms and development of new technologies and new drugs for the treatment of osteoporosis in the future.

Although degeneration of the nucleus pulposus (NP) is a major contributor to intervertebral disc degeneration (IVDD) and low back pain, the underlying molecular complexity and cellular heterogeneity remain poorly understood. Here, a comprehensive single‐cell resolution transcript landscape of human NP is reported. Six novel human NP cells (NPCs) populations are identified by their distinct molecular signatures. The potential functional differences among NPC subpopulations are analyzed. Predictive transcripts, transcriptional factors, and signal pathways with respect to degeneration grades are explored. It is reported that fibroNPCs is the subpopulation for end‐stage degeneration. CD90+NPCs are observed to be progenitor cells in degenerative NP tissues. NP‐infiltrating immune cells comprise a previously unrecognized diversity of cell types, including granulocytic myeloid‐derived suppressor cells (G‐MDSCs). Integrin αM (CD11b) and oxidized low density lipoprotein receptor 1 (OLR1) as surface markers of NP‐derived G‐MDSCs are uncovered. The G‐MDSCs are found to be enriched in mildly degenerated (grade II and III) NP tissues compared to severely degenerated (grade IV and V) NP tissues. Their immunosuppressive function and alleviation effects on NPCs’ matrix degradation are revealed in vitro. Collectively, this study reveals the NPC‐type complexity and phenotypic characteristics in NP, thereby providing new insights and clues for IVDD treatment.

Degenerative cervical myelopathy (DCM), earlier referred to as cervical spondylotic myelopathy (CSM), is the most common and serious neurological disorder in the elderly population caused by chronic progressive compression or irritation of the spinal cord in the neck. The clinical features of DCM include localised neck pain and functional impairment of motor function in the arms, fingers and hands. If left untreated, this can lead to significant and permanent nerve damage including paralysis and death. Despite recent advancements in understanding the DCM pathology, prognosis remains poor and little is known about the molecular mechanisms underlying its pathogenesis. Moreover, there is scant evidence for the best treatment suitable for DCM patients. Decompressive surgery remains the most effective long-term treatment for this pathology, although the decision of when to perform such a procedure remains challenging. Given the fact that the aged population in the world is continuously increasing, DCM is posing a formidable challenge that needs urgent attention. Here, in this comprehensive review, we discuss the current knowledge of DCM pathology, including epidemiology, diagnosis, natural history, pathophysiology, risk factors, molecular features and treatment options. In addition to describing different scoring and classification systems used by clinicians in diagnosing DCM, we also highlight how advanced imaging techniques are being used to study the disease process. Last but not the least, we discuss several molecular underpinnings of DCM aetiology, including the cells involved and the pathways and molecules that are hallmarks of this disease.

Although cigarette smoke (CS) and low back pain (LBP) are common worldwide, their correlations and the mechanisms of action remain unclear. We had shown that excessive activation of Mast Cells (MCs) and their proteases play key roles in CS associated diseases, like asthma, chronic obstructive pulmonary disease (COPD), blood coagulation and lung cancer. Previous studies also show that MCs and their proteases induce degenerative musculoskeletal disease. By using mice custom-designed smoke-exposure system, we demonstrated that CS results in intervertebral disc (IVDs) degeneration and the release of MC-restricted tetramer tryptases (TT) inside the IVDs. TT was found to regulate the expression of methyltransferase 14 (METTL14) at the epigenetic level by inducing N6-methyladenosine (m6A) deposition in the 3'-untranslated region (3'-UTR) of the transcript that encodes DIX Domain Containing 1 (DIXDC1). That reaction increases the mRNA stability and expression of Dixdc1. DIXDC1 functionally interacts with 'Disrupted in Schizophrenia-1' (DISC1) to accelerate the degeneration and senescence of nucleus pulposus (NP) cells by activating a canonical Wnt pathway. Our study demonstrates the association between CS, MC-derived TTs, and LBP. These findings raise the possibility that METTL14-medicated DIXDC1 m6A modification could serve as a potential therapeutic target to block the development of degeneration of the NP in LBP patients.