Micrornas as Versatile Tools in Musculoskeletal Tissue Engineering

Musculoskeletal injuries, encompassing tendon, bone, and cartilage damage, pose significant challenges to regenerative medicine due to the intricate interplay of mechanical, cellular, and molecular factors governing tissue repair. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression post-transcriptionally, have emerged as potent regulators of tissue homeostasis, remodeling, and healing. By targeting multiple genes and pathways, miRNAs hold immense promise as therapeutic and diagnostic tools across the musculoskeletal spectrum. In tendon tissue engineering, miRNAs such as the miR-29 family have been extensively investigated for their role in regulating extracellular matrix remodeling. miR-29a and miR-29b modulate collagen production and fibrosis-related pathways, promoting balanced healing in preclinical models. Furthemore, our group has reported the upregulation of the antifibrotic miRNAs miR-16-5p and miR-133a-3p in the site of injury of tendon-to-bone entheses, potentially modulating scar formation and fibrogenesis. Moreover, hMSCs transfected with miRNA-16-5p mimics showed decreased expression of fibrosis markers in vitro, in a tendon-mimetic environment. In the context of bone tissue, we have identified specific miRNAs associated with fracture healing phases, patient age, and multitrauma. Additionally, miRNAs such as miR-21 and miR-31 are pivotal in regulating osteogenic differentiation, bone formation, and remodeling. These miRNAs interact with pathways like BMP/Smad and Wnt/β-catenin, influencing bone regeneration in both physiological and pathological contexts. Furthermore, miR-26a has been shown to enhance osteoblast function while mitigating osteoclast activity, underscoring its therapeutic potential for bone repair. Similarly, miRNAs like miR-140 and miR-145, among others, are currently been investigated in cartilage regeneration, as they are thought to regulate chondrogenic differentiation and extracellular matrix production. miR-140-3p, for instance, modulates cartilage homeostasis by targeting ADAMTS5, a key enzyme involved in cartilage degradation. Modulation of such miRNAs offers promising avenues for treating degenerative diseases like osteoarthritis. Collectively, these findings position miRNAs as versatile regulators across musculoskeletal tissues. By integrating miRNA-based strategies with advances in biomaterials, mechanobiology, and tissue engineering, it is possible to develop novel therapeutic approaches and diagnostic tools to enhance healing, reduce fibrosis, and improve patient outcomes. Future studies unraveling the dynamic roles of miRNAs in the context of mechanical forces and cellular interactions will further revolutionize regenerative medicine, addressing critical unmet clinical needs.