eIF2α–ATF4 Pathway Activated by a Change in the Calcium Environment Participates in BCP-Mediated Bone Regeneration

Biphasic calcium phosphate (BCP) ceramic is a classic bone void filler and a common basis of new materials for bone defect repair. However, the specific mechanism of BCP in osteogenesis has not been fully elucidated. Endoplasmic reticulum stress (ERs) and the subsequent PERK–eIF2α–ATF4 pathway can be activated by various factors, including trauma and intracellular calcium changes, and therefore worth exploring as a potential mechanism in BCP-mediated bone repair. Herein, a rat lateral femoral epicondyle defect model in vivo and a simulated BCP-mediated calcium environment in vitro were constructed for the analysis of BCP-related osteogenesis and the activation of ERs and the eIF2α–ATF4 pathway. An inhibitor of eIF2α dephosphorylation (salubrinal) was also used to explore the effect of the eIF2α–ATF4 pathway on BCP-mediated bone regeneration. The results showed that the ERs and eIF2α–ATF4 pathway activation were observed during 4 weeks of bone repair, with a rapid but brief increase immediately after artificial defect surgery and a re-increase after 4 weeks with the resorption of BCP materials. Mild ERs and the activated eIF2α induced by the calcium changes mediated by BCP regulated the expression of osteogenic-related proteins and had an important role during the defect repair. In conclusion, the eIF2α–ATF4 pathway activated by a change in the calcium environment participates in BCP-mediated bone regeneration. eIF2α–ATF4 and ERs could provide new directions for further studies on new materials in bone tissue engineering.