Senescent cells impair fracture repair through elevating ubiquitin-proteasome system activity in aged mice.

Abstract

Senescent cells accumulate in multiple tissues with aging. Depletion of senescent cells benefits the aging related disease, such as aging bone fracture. However, the molecular mechanisms by which senescent cells regulate their neighboring bone cells are still not well-known. We reported that proteasome inhibitor enhanced fracture repair in aged mice. Senescent cells are major source of chronic inflammatory cytokines, which in turn induced protein ubiquitination. We reported that PDGFR{beta} was one of the highly ubiquitinated proteins in mesenchymal progenitors (MPCs) and TGF{beta} was the most increased SASP. In the current study, we found TGF{beta} induced PDGFR{beta} ubiquitination and proteasomal degradation through its E3 ligases. TGF{beta} neutralizing antibody blocked the inhibited callus derived MPC growth and increased Ub-PDGFR{beta} by senescent cells, which could be further prevented PDGFR{beta} inhibitor. These findings suggested senescent cells derived TGF{beta} impaired fracture repair in aged mice through elevating ubiquitination of PDGFR{beta}. The discovery of TGF{beta}-PDGFR{beta} pathway triggered by senescent cells opens avenues for optimizing treatment strategies for aging related disease by combination with the ligand of PDGFR{beta}.