This Column focuses on the fundamental biological processes and theoretical frameworks that govern musculoskeletal health and disease. It invites research that elucidates cellular and molecular mechanisms underlying bone development, remodeling, repair, and degeneration, as well as the pathogenesis of orthopedic disorders including osteoporosis, osteoarthritis, fractures, spinal conditions, and implant-related complications. The Column also considers theoretical models, computational simulations, and systems biology approaches that advance mechanistic understanding of orthopedic biology. The goal is to deepen insight into the causal pathways of musculoskeletal diseases and to identify translational opportunities for mechanism-based diagnosis, prevention, and therapeutic intervention in orthopedics.