Ribosome heterogeneity and specialisation in musculoskeletal physiology and pathology

Abstract Musculoskeletal (MSK) tissues are highly dynamic systems that rely on tightly regulated protein synthesis to maintain homeostasis, structural integrity, adapt to physiological stimuli, and respond to injury. Deregulation of protein synthesis is implicated in a wide range of MSK pathologies. At the core of protein synthesis are ribosomes, complex molecular nanomachines that translate mRNAs and generate proteins. Once considered uniform entities passively exerting their function, ribosomes are now recognised to be heterogeneous in their composition and capable of specialised functions. These emerging concepts of ribosome heterogeneity and specialisation are increasingly recognised as key regulators of physiological and pathological cellular processes across fields. Although the MSK field has yet to fully embrace and integrate ribosome-centred research, accumulating evidence suggests that ribosome heterogeneity and specialisation might have profound implications for MSK (patho)biology. In this review, we summarise the emerging data across MSK tissues (bone, skeletal muscle, articular cartilage, tendons, and ligaments), highlighting roles of ribosomes in supporting development, maintaining homeostasis, facilitating cellular and tissue functions and adaptations, but also driving pathological changes and disease progression. Furthermore, we also outline recent key technological and methodological advances that are critical for uncovering the full scope, significance, and dynamic regulation of ribosome heterogeneity and specialisation in MSK (patho)biology. As the field moves forward, ribosome-centred research holds great promise in revealing new mechanisms underlying MSK biology and identifying novel therapeutic targets.