bioRxiv2026
Many microRNAs (miRNAs) regulate tissue remodeling, cellular plasticity, and repair across evolutionarily distant vertebrate lineages that are capable of regenerating appendages such as amputated limbs, fins, and antlers, as well as in human articular cartilage responding to injury. These miRNAs often belong to the same families and exert conserved, though occasionally inverted, regulatory effects. This strong cross-species overlap motivates the present literature-derived analysis. Osteoarthritis (OA), the most prevalent joint disease, still lacks disease-modifying therapies, in part because of the longstanding assumption that adult mammalian cartilage demonstrates no intrinsic reparative capacity. Yet human cartilage retains a latent repair program activated by mechanical and inflammatory stress. Some injured or degenerating joints may never be clinically recognized as osteoarthritic because their intrinsic repair capacity is sufficient to restore tissue integrity; in others, where repair capacity is diminished or damage exceeds it, the repair program is insufficient and OA becomes clinically manifest. MiRNAs are established post-transcriptional regulators of cartilage homeostasis, degeneration, and appendage regeneration, yet because the OA and regeneration research fields have advanced largely independently, the insights available at their intersection have gone unrecognized. To close this gap, we systematically mined both literatures to construct an auto-updating, cross-referenced atlas of OA- and appendage regeneration-associated miRNAs. Integrating these datasets identified a core set of shared miRNA families, delineated miRNAs unique to each field, and mapped convergent families onto common pathways governing matrix remodeling, dedifferentiation, senescence, and inflammation. We propose that regeneration-competent species can inform the identification of therapeutic miRNAs, such as miR-133, miR-21, and let-7, capable of activating endogenous cartilage repair. Collectively, this synthesis and its accompanying web-based miRNA atlas (https://mirnaatlas.shinyapps.io/mirnaatlas/) establish a comparative framework for regenerative miRNA biology and provide a continually updated resource to accelerate discovery of disease-modifying, RNA-based therapies for OA.