Endoplasmic-reticulum Stress In The Pathogenesis Of Aseptic Loosening Of The Prosthesis

Although total hip arthroplasty is one of the most successful surgical procedures, aseptic loosening, which results from particle-induced osteolysis, remains the most common cause of revision of major arthroplasties. To investigate the pathogenesis of prosthesis with aseptic loosening is important for prevention and the therapy of aseptic loosening. Recent studies have found that Endoplasmic-reticulum stress is involved in the initiationof the inflammation, which is widely accepted to play a key role in particle-induced osteolysis, but whether Endoplasmic-reticulum stress being participated in the aseptic loosening has not yet been clarified.In this paper we hypothesized that endoplasmic reticulum (ER) stress in macrophages induced by wear particles was one of the reasons for particle-induced osteolysis (PIO) in total hip arthroplasty (THA) failure. Firstly, a macrophages-like cells Raw264.7 was used for experiment in vitro. The expression of IRE1-α,GRP78/Bip and CHOP, ER stress markers, was dramatically increased when Raw264.7 was treated with Ti or CoCrMo wear-debris, indicating that TiPs and CoPs created ER stress in Raw264.7 cells. To address the effect of ER stress on inflammatory cytokine expression, the expression of IL-6, TNF-α and IL-1 β was detected when Raw264.7 was treated with Ti or CoCrMo particles only, and cotreatment of these particles with 4-PBA, a classic ER stress inhibitor. Ti or CoCrMo particles markedly induce cytokins upregulation, which was dose-dependently inhibited by 4-PBA. These indicate that ER stress is implicated in particle-induced inflammatory cytokins expression.To determine whether ER stress is induced in vivo by wear particles, we evaluated dates from different experiments in vivo including western blotting, the expression of inflammatory cytokines, toluidine blue staining and TRAP staining of calvaria. The results shows that particles treatment markedly increased ER stress marker protein, inflammatory cytokines, the bone resorption and the activity of osteoclasts. More impressing findings were when the animal models treated with 4-PBA, these upregulations were reversed.The specimens from the patient with aseptic loosening showed higher level of ER stress markers IRE1-α, Bip and CHOP and TRAP activity compared to the control tissue. These results suggested a strong association between ER stress and aseptic loosening in human patients.In summary, one of the mechanism of aseptic loosening may be that the wear particles are phagocytised by macrophages and stimulate RE stress in these cells, ER stress-mediated the secretion of various inflammatory cytokines and chemokines, such as IL-6, TNF-α and IL-1β, which mediated the differentiation and activation of osteoclasts and result in pathological bone resorption. Blocking ER stress pathwaymay with specific inhibitors lead to novel therapeutic approaches for the treatment of aseptic prosthesis loosening.