Stem Cells and their Key Derivatives in Degenerative Musculoskeletal Diseases.

Degenerative musculoskeletal diseases such as osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IVDD) represent a growing global health challenge, causing disability, pain, and socioeconomic burden. Traditional therapies remain largely palliative, underscoring the urgent need for regenerative approaches. Mesenchymal stem cells (MSCs) are promising tools due to their capacity for multilineage differentiation, immunomodulation, and paracrine signaling. However, challenges including heterogeneity, low engraftment, and manufacturing complexity limit their clinical translation. Increasingly, extracellular vesicles (EVs) derived from MSCs have been recognized as the principal mediators of their therapeutic effects. MSC-derived-EVs (MSC-EVs) provide a safer, cell-free platform capable of regulating immune responses, promoting tissue regeneration, and delivering bioactive cargos that restore bone, cartilage, and disc homeostasis. Preclinical and early clinical data highlight their potential as next-generation therapeutics. The aim of this review is to provide valuable insights into the development and evaluation of MSCs and MSC-EVs in OA, OP, and IVDD thereby accelerating clinical translation and improving patient outcomes.