Novel Insights into the Links between N6-Methyladenosine and Regulated Cell Death in Musculoskeletal Diseases.

Musculoskeletal diseases (MSDs), including osteoarthritis (OA), osteosarcoma (OS), multiple myeloma (MM), intervertebral disc degeneration (IDD), osteoporosis (OP), and rheumatoid arthritis (RA), present noteworthy obstacles associated with pain, disability, and impaired quality of life on a global scale. In recent years, it has become increasingly apparent that N6-methyladenosine (m6A) is a key regulator in the expression of genes in a multitude of biological processes. m6A is composed of 0.1-0.4% adenylate residues, especially at the beginning of 3'-UTR near the translation stop codon. The m6A regulator can be classified into three types, namely the "writer", "reader", and "eraser". Studies have shown that the epigenetic modulation of m6A influences mRNA processing, nuclear export, translation, and splicing. Regulated cell death (RCD) is the autonomous and orderly death of cells under genetic control to maintain the stability of the internal environment. Moreover, distorted RCDs are widely used to influence the course of various diseases and receiving increasing attention from researchers. In the past few years, increasing evidence has indicated that m6A can regulate gene expression and thus influence different RCD processes, which has a central role in the etiology and evolution of MSDs. The RCDs currently confirmed to be associated with m6A are autophagy-dependent cell death, apoptosis, necroptosis, pyroptosis, ferroptosis, immunogenic cell death, NETotic cell death and oxeiptosis. The m6A-RCD axis can regulate the inflammatory response in chondrocytes and the invasive and migratory of MM cells to bone remodeling capacity, thereby influencing the development of MSDs. This review gives a complete overview of the regulatory functions on the m6A-RCD axis across muscle, bone, and cartilage. In addition, we also discuss recent advances in the control of RCD by m6A-targeted factors and explore the clinical application prospects of therapies targeting the m6A-RCD in MSD prevention and treatment. These may provide new ideas and directions for understanding the pathophysiological mechanism of MSDs and the clinical prevention and treatment of these diseases.

Roles and mechanisms of copper homeostasis and cuproptosis in osteoarticular diseases.

Copper is an essential trace element in the human body that is extensively distributed throughout various tissues. The appropriate level of copper is crucial to maintaining the life activities of the human body, and the excess and deficiency of copper can lead to various diseases. The copper levels in the human body are regulated by copper homeostasis, which maintains appropriate levels of copper in tissues and cells by controlling its absorption, transport, and storage. Cuproptosis is a distinct form of cell death induced by the excessive accumulation of intracellular copper. Copper homeostasis and cuproptosis has recently elicited increased attention in the realm of human health. Cuproptosis has emerged as a promising avenue for cancer therapy. Studies concerning osteoarticular diseases have elucidated the intricate interplay among copper homeostasis, cuproptosis, and the onset of osteoarticular diseases. Copper dysregulation and cuproptosis cause abnormal bone and cartilage metabolism, affecting related cells. This phenomenon assumes a critical role in the pathophysiological processes underpinning various osteoarticular diseases, with implications for inflammatory and immune responses. While early Cu-modulating agents have shown promise in clinical settings, additional research and advancements are warranted to enhance their efficacy. In this review, we summarize the effects and potential mechanisms of copper homeostasis and cuproptosis on bone and cartilage, as well as their regulatory roles in the pathological mechanism of osteoarticular diseases (e.g., osteosarcoma (OS), osteoarthritis (OA), and rheumatoid arthritis (RA)). We also discuss the clinical-application prospects of copper-targeting strategy, which may provide new ideas for the diagnosis and treatment of osteoarticular diseases.