Salubrinal-mediated activation of eIF2α signaling improves oxidative stress-induced BMSCs senescence and senile osteoporosis.

ABSTRACT

Bone cells of various lineages become senescent in bone microenvironment. Senotherapies that clear the senescent bone cells improve bone microarchitecture of aged bones. However, the mechanisms underlie for the formation and maintenance of senescent bone cells are largely unknown. Here, we focus on the relationship between endoplasmic reticulum stress (ER stress)-activated unfolded protein response (UPR) signaling and cellular senescence of bone marrow mesenchymal stem cells (BMSCs). The PKR-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2 α(eIF2α) signaling branch was specifically activated and tightly regulated in senescent BMSCs induced by hydrogen peroxide (H2O2). However, blocking PERK-eIF2α signaling with AMG'44 could not reverse the cellular senescence phenotype of senescent BMSCs. Treated the senescent cells with salubrinal, an inhibitor for dephosphorylation of eIF2α, decreased SA-ß-Gal positive cells and the expression of markers for cellular senescence. Moreover, salubrinal enhanced the apoptosis of senescent BMSCs and upregulated expression of Chop and BIM. Furthermore, salubrinal treatment significantly improved the osteogenesis capacity of senescent BMSCs as reflected by the increase of Alp, Runx2 and Osteocalcin, the formation of Alp-positive staining cells and matrix mineralization. Salubrinal administration results in significant recovery in the bone microarchitecture of senile SAMP6 mice. Taken together, our data reveal an undefined role of PERK-eIF2α signaling in the maintenance of cellular senescent phenotype in BMSCs. The activation of eIF2α signaling with salubrinal is helpful for the clearance of senescent BMSCs and the improvement of bone integrity of aged mice.