FGF8 induces bone and joint regeneration at digit amputation wounds in neonate mice

Due to increases in vascular diseases, the incidence of limb loss is predicted to more than double in the next quarter century. Therefore, developing a greater understanding of the latent regenerative capacity in mammals is a significant and growing goal. Mammals, including humans and mice, have limited regenerative capacity following limb amputation, with regenerative responses restricted to amputations transecting the distal digit tip (P3). Unlike P3, amputations of the adjacent skeletal segment, the middle phalanx, P2, are non-regenerative and result in bone truncation and soft tissue scar formation. As such, P2 amputation is a simple yet powerful model to test strategies for inducing mammalian musculoskeletal regeneration from an otherwise non-regenerative amputation plane. Here, we report that Fibroblast Growth Factor 8 (FGF8) drives synovial joint regeneration at P2 amputation wounds in neonate mice. This response is characterized by the regeneration of a synovial cavity, a skeletal nodule lined with articular cartilage, and tendon and ligament regeneration. FGF8 also induces cartilage formation on the P2 stump that serves as a template for partial P2 bone regeneration, thus FGF8 drives the composite regeneration of stump and joint tissues. FGF8-induced joint regeneration is associated with the upregulation of several, but not all, genes that characterize joint development, and is morphologically distinct from digit joint development. Lineage tracing studies demonstrate that cells at the amputation wound contribute to the regenerated joint structures. These studies provide evidence that the otherwise non-regenerative P2 amputation wound possesses tremendous regenerative capacity that is dormant under normal circumstances.