Anabolic indices of matrix proteins identify regenerative small RNA intrinsic to human cartilage

Some vertebrates regenerate appendages through the action of small noncoding RNAs (smRNAs) expressed in their blastema. Inspired by these models, we investigated whether similar smRNA-mediated mechanisms might contribute to the intrinsic repair capacity of human cartilage. Although humans lack the capacity to regenerate entire limbs, digit tip regrowth and joint cartilage repair following joint distraction suggest latent regenerative potential. Using mass spectrometry and RNA sequencing, we quantified anabolic indices of cartilage extracellular matrix proteins and identified 69 smRNAs correlated with cartilage regeneration in osteoarthritis-six concordantly regulated across species (human, axolotl, zebrafish, and bichir)-including microRNA 21 (miR-21). miR-21 enhanced the expression of key cartilage formation genes, reduced cartilage degradation, and suppressed cytokine secretion from human cartilage and chondrocytes. In contrast to the knee and hip, ankle cartilage exhibited regenerative capacity under osteoarthritic stress, offering a model for a regeneration-permissive joint environment that could inform osteoarthritis therapies.