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

Abstract

AbstractSenescent 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 PDGFRβ was one of the highly ubiquitinated proteins in mesenchymal progenitors (MPCs) and TGFβ was the most increased SASP. In the current study, we found TGFβ induced PDGFRβ ubiquitination and proteasomal degradation through its E3 ligases. TGFβ neutralizing antibody blocked the inhibited callus derived MPC growth and increased Ub-PDGFRβ by senescent cells, which could be further prevented PDGFRβ inhibitor. These findings suggested senescent cells derived TGFβ impaired fracture repair in aged mice through elevating ubiquitination of PDGFRβ. The discovery of TGFβ-PDGFRβ pathway triggered by senescent cells opens avenues for optimizing treatment strategies for aging related disease by combination with the ligand of PDGFRβ.