Advancing musculoskeletal organoids research: Overcoming barriers to reduce animal model dependency

Musculoskeletal (MSK) disorders represent a leading cause of disability worldwide, with their incidence increasing steadily each year. While animal models have been instrumental in replicating various aspects of MSK pathologies, they face significant limitations, including interspecies variations, ethical concerns, and prolonged modeling timelines. The emergence of MSK organoids presents promising complementary models for pathophysiological research, disease modeling, drug screening, and regenerative medicine. As a valuable adjunct for traditional two-dimensional cultures and animal experiments, organoids provide novel mechanistic insights into MSK biology in a more physiologically relevant context. This review provides a comprehensive overview of current modeling strategies for MSK diseases and highlights the potential of organoids to reduce reliance on animal models. We critically assess the advantages and limitations of MSK organoids in disease recapitulation, identify key challenges in their development, and propose potential strategies for refinement. Finally, future directions and opportunities in this rapidly evolving field have been discussed.