Regulated cell death in musculoskeletal development, homeostasis, and diseases

Regulated cell death (RCD) is a fundamental biological process that plays critical roles in regulating organogenesis and maintaining homeostasis under physiological conditions, and when cells are exposed to detrimental microenvironment, it contributes to the initiation and progression of pathological changes. Musculoskeletal disorders and diseases, such as osteoporosis, osteoarthritis, and intervertebral disk degeneration, have become public health problems worldwide, owing to their high prevalence and heavy economic burden. RCD is closely associated with the pathogenesis of skeletal disorders and diseases. Given the dedicated but controllable molecular machinery involved in RCD, studying the signal pathways and molecular mechanisms of RCD holds promise for the development of preventative and therapeutic targets. Over the last two decades, distinct modes and concepts of RCD have been proposed, including mitochondrial permeability transition-driven necrosis, lysosome-dependent cell death, pyroptosis, NETotic cell death, immunogenic cell death, necroptosis, entotic cell death, parthanatos, ferroptosis, autophagy-dependent cell death, alkaliptosis, oxeiptosis, PANoptosis, and cuproptosis. In this review, we aim to provide an up-to-date understanding of the roles of different RCD subroutines in maintaining the health and function of bones, cartilage and intervertebral discs. We will highlight their specific molecular mechanisms and cross-talks, hence offering valuable insights into further research directions.