Proteoglycan 4 (PRG4), also known as lubricin, plays a critical role in maintaining joint homeostasis by reducing friction between articular cartilage surfaces and preventing cartilage degradation. Its deficiency leads to early-onset osteoarthritis (OA), while overexpression can protect against cartilage degeneration. Beyond its lubricating properties, PRG4 exerts anti-inflammatory effects by interacting with Toll-like receptors, modulating inflammatory responses within the joint. The expression of Prg4 is regulated by various factors, including mechanical stimuli, inflammatory cytokines, transcription factors such as Creb5 and FoxO, and signaling pathways like TGF-β, EGFR, and Wnt/β-catenin. Therapeutic strategies targeting PRG4 in OA have shown promising results, including recombinant PRG4 protein injections, gene therapies, and small molecules that enhance endogenous Prg4 expression or mimic its function. Further research into the molecular mechanisms regulating Prg4 expression will be essential in developing more effective OA treatments. Understanding the interplay between Prg4 and other signaling pathways could reveal novel therapeutic targets. Additionally, advancements in gene therapy and biomaterials designed to deliver PRG4 in a controlled manner may hold potential for the long-term management of OA, improving patient outcomes and delaying disease progression.

Extracellular Vesicles (EVs), nanoscale membrane‐bound cell‐released structures, are vital for intercellular communication and material transport. Their role in musculoskeletal health and diseases has recently drawn significant attention. This review focuses on the latest EV research in musculoskeletal diseases, including their roles in disease progression and potential as biomarkers and therapies. Musculoskeletal disorders are the third‐leading cause of global disability‐adjusted life‐years among adolescents and young adults. Current treatments face issues like limited tissue regeneration and poor drug targeting. With their natural messenger function and low immunogenicity, EVs have become a research focus. However, their action mechanisms in the musculoskeletal system remain un‐systematically understood. This paper reviews EVs’ role in musculoskeletal diseases. It covers classification, biogenesis, release, internalization, cargo and their involvement in muscle cell processes, joint diseases, bone metabolism and disc degeneration. It also explores EVs’ role in musculoskeletal crosstalk and their potential as therapeutic agents and drug carriers through engineering with biomaterials. Future research should delve deeper into EV action mechanisms for better treatments. Overall, while EVs offer new treatment strategies for musculoskeletal diseases, more research is needed to overcome technical and clinical barriers.