Abstract

Macrophage apoptosis and inflammation in interface membrane have been shown to play a significant role in the pathogenesis of osteolysis. However, osteoblasts have not been fully explored as a participant in the process of osteolysis, despite their critical role in bone growth, remodeling and maintenance. The purpose of our study was to identify whether endoplasmic reticulum (ER) stress participates in particle-induced osteolysis (PIO), osteoblasts apoptosis and inflammation within osteolytic bone tissues in PIO animal models. We examined the histopathologic changes of osteolysis and the expression of ER stress-related apoptotic markers (Ca2+, IRE1-α, PERK, GRP78/Bip, CHOP, JNK and Caspase-12) and inflammatory markers (TNF-α, IL-1β, and IL-6; ROS and Ca2+; NF-κB and c-Fos), and analyzed apoptosis and apoptotic regulators (Bcl-2 and Bax) within the osteolytic bone tissues. Our results demonstrated that wear particles were able to induce ER stress, and were associated with the inflammation and apoptosis of osteoblasts in vivo and vitro. Blocking ER stress with 4-PBA dramatically decreased particle-induced osteolysis symptoms, lessened the infiltration of inflammatory cells, reduced the inflammatory response, diminished the capability of osteoclastogenesis, and promoted the differentiation of osteoblasts. However, the ER stress blocker unexpectedly aggravated cell death of osteoblasts, which was of vital importance to the osteanagenesis of the ostolytic and absorptive bone. Given that the ER chaperone conforms to the definition of true moonlighting proteins with two quite distinct roles in nucleus and cell surface, making modulators of ER potentially attractive targets for therapeutics discovery. Thus, a better understanding of the mechanisms that orchestrate the ER may help to devise future strategies of safely modulating this process for therapeutic benefit.

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