Alternative Splicing: A Critical Regulator in Human Bone Biology and Tumor Progression

Alternative splicing (AS) is the central mechanism of transcriptional regulation and generates diverse splice variants that influence protein structure, function, and intracellular activity. AS plays critical roles in tissue differentiation, organ development, and disease progression. This review focuses on the pivotal roles of AS in bone biology, highlighting its regulatory effects on osteoblasts, osteoclasts, chondrocytes, bone matrix remodeling, and bone remodeling, as well as the involvement of AS-related RNA-binding proteins in these processes. We also emphasize bone-specific AS events and their physiological importance in skeletal development and maintenance. Furthermore, the pathological role of AS is emphasized in bone-related tumors such as osteosarcoma, Ewing sarcoma, and chondrosarcoma. This review also explores aberrant AS mechanisms in bone metastatic cancers, including prostate, bladder, and breast cancers, with an in-depth analysis of their roles in tumor progression and alterations in the bone microenvironment. This review provides a comprehensive perspective on how AS factors, signaling pathways, and mechanical stimulation collaboratively regulate bone cells under both physiological and pathological conditions, paving the way for identifying potential intervention strategies. The mechanisms of AS in other pathological bone conditions, such as osteoporosis, osteoarthritis, and hereditary bone disorders, are also summarized. The potential applications of targeting AS in the diagnosis and treatment of bone diseases are discussed, offering insights into the underlying mechanisms and clinical translational potential.