Cellular metabolism at the crossroads of skeletal regeneration

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Limb regeneration after injury is a sophisticated and energetically expensive process. In this process, progenitor proliferation, osteoblast differentiation and mineral deposition all require sufficient supplies of biological building blocks and ATP(1-5). However, the contribution of cell metabolism and its genetic control of skeletal regeneration is largely unknown, representing a major knowledge gap. Using the established mouse digit tip amputation model, we found that mice exhibit impaired regeneration during aging, and that this impairment is linked to increased expression of glycolysis and oxidative phosphorylation (OxPhos) genes, compared to young mice. These exciting preliminary results have led us to investigate the metabolic and genetic mechanisms that underlie skeletal regeneration. Our preliminary findings support that skeletal regeneration is metabolism-dependent and can be manipulated by exogenous metabolites and gene expression, respectively. These data suggest that administration of oxaloacetate (OAA), a pro-glycolytic and pro-respiratory metabolite, increases regenerated bone volume and thickness in a mouse model. Alternatively, modulation of collagen triple helix repeat containing 1 (Cthrc1) also alters skeletal regeneration. Cthrc1 is specifically expressed in the blastema, the dedifferentiated tissue structure central to regeneration, and Cthrc1-/- mice demonstrated impaired regeneration and dysregulated cell metabolism. Moreover, our preliminary data show that treatment with OAA increases Cthrc1 expression, reinforcing a direct link between metabolism and genetic control. We hypothesize that a finely tuned interaction between cell metabolism and genetic control synergistically regulates cell function, and that this interaction can be manipulated both exogenously (OAA) and at a gene level (Cthrc1) to modulate regenerative outcomes.