Reintegration of blastema and stump by reciprocal interaction for functional joint regeneration in frogs

Previous studies suggested the importance of the reciprocal interactions between residual tissues, which we refer to here as the “stump”, and the newly formed tissues, referred to as the “blastema”, for achieving functional joint regeneration after amputation at the elbow joint level in newts. This reciprocal interaction during regeneration was named “reintegration”. When this reintegration mechanism was evoked in the frog Xenopus leavis, regeneration of a functional elbow joint was induced. Interestingly, degradation of extracellular matrix (ECM) in the remaining joint articular cartilage was observed during regeneration in both newts and frogs. Histological and gene expression analyses suggested that the degradation of Type II collagen in the cartilage of the articular head might be performed by matrix metalloproteases (Mmps) that were transiently expressed after amputation. Here we found that fibroblast growth factor (Fgf) induced Mmps expression in the cartilage of the articular head. These results support the possibility that the Fgf signal induces ECM degradation in joint tissues via Mmps expression and that the ECM degradation and subsequent bone morphogenetic protein (Bmp) secretion promote cell proliferation, migration, and differentiation of the cells in the blastema to achieve functional joint regeneration.