Role and mechanism of endoplasmic reticulum stress response induced by wear particles in osteolysis / 中国骨伤

OBJECTIVE@#To analyze the role of endoplasmic reticulum stress response in the development of osteoblast apoptosis and osteolysis in osteolytic bone tissue, and to explore the causes of artificial joint loosening, so as to provide new ideas and theoretical basis for the prevention and treatment of artificial joint loosening.@*METHODS@#The animal model of osteolysis induced by wear particles was established by mouse skull, and randomly divided into 4 groups, 7 rats in each group:group 1, blank control group;group 2, wear particles tial6v4 nano alloy powder (TiNPs) group;group 3, endoplasmic reticulum stress response positive control (TiNPs+Tg) group; group 4, endoplasmic reticulum stress response inhibitor (TiNPs+4-PBA) group. The pathological changes of osteolysis were observed by toluidine blue staining, HE staining and ALP staining;the expression of endoplasmic reticulum stress response marker protein was detected by Western Blotting;the apoptosis of osteoblasts in osteolytic skull tissue was detected by TUNEL and Caspase-3 immunohistochemistry.@*RESULTS@#Wear particles TiNPs can induce osteolysis in vitro, aggravate the infiltration of inflammatory cells and inhibit the differentiation and maturation of osteoblasts. At the same time, wear particles can also up regulate the markers of endoplasmic reticulum stress response and promote the apoptosis of osteoblasts in osteolytic bone tissue. After adding 4-PBA, an inhibitor of endoplasmic reticulum stress (4-PBA), on the basis of wear particles TiNPs, the symptoms of osteolysis were significantly relieved, bone erosion and inflammatory infiltration were significantly reduced, the differentiation and maturation of osteoblasts were improved, the number of apoptotic osteoblasts decreased sharply, and the expression of endoplasmic reticulum stress marker protein gradually decreased.@*CONCLUSION@#Endoplasmic reticulum stress is involved in the formation of osteolysis and plays an important role in the occurrence and development of osteolysis. At the same time, endoplasmic reticulum stress can be used as a new therapeutic target to provide new ideas and methods for clinical reversal or treatment of osteolysis and aseptic loosening.

Medication-related osteonecrosis of the jaw. Introduction of a new modified experimental model

ABSTRACT PURPOSE : To evaluate a modified experimental model for medication-related osteonecrosis of the jaw (MRONJ) through the upper right central incisor extraction followed by intravenous bisphosphonate administration. METHODS: Forty five rats underwent the upper right central incisor tooth extraction were divided in 2 groups: Group I - experimental group, 30 rats received an intravenous administration protocol of zoledronic acid 35μg/kg into the tail vein every two weeks, totalizing four administrations, during eight weeks of administration, previously the extraction, and Group II - control group, 15 rats didn't received any medication before extraction. The groups were subdivided in postoperative periods: 14/28/42 days. Clinical analysis and microtomography were performed to verify the presence of osteonecrosis. In addition, descritive histological analysis of hematoxylin-eosin stained sections was performed to evaluate the presence of osteonecrosis or necrotic foci. RESULTS: Twelve (40%) rats, from experimental group, showed clinical signs of MRONJ (p=0.005), however, all samples showed imaginologic findings like osteolysis and loss of integrity of the cellular walls (p≤0.001). Microscopic evaluation revealed osteonecrosis areas with microbial colonies and inflammatory infiltrate (p≤0.001). In the control group, all animals presented the chronology of a normal wound healing. CONCLUSIONS: The presence of medication-related osteonecrosis of the jaw after maxillary central incisor extraction in rats. This new experimental model may be considered an option for the study of MRONJ.

Inhibitory effect of (-)-epigallocatechin gallate on titanium particle-induced TNF-alpha release and in vivo osteolysis

Tumor necrosis factor-alpha (TNF-alpha) and inflammatory cytokines released from activated macrophages in response to particulate debris greatly impact periprosthetic bone loss and consequent implant failure. In the present study, we found that a major polyphenolic component of green tea, (-)-epigallocatechin gallate (EGCG), inhibited Ti particle-induced TNF-alpha release in macrophages in vitro and calvarial osteolysis in vivo. The Ti stimulation of macrophages released TNF-alpha in a dose- and time-dependent manner, and EGCG substantially suppressed Ti particle-induced TNF-alpha release. Analysis of signaling pathway showed that EGCG inhibited the Ti-induced c-Jun N-terminus kinase (JNK) activation and inhibitory kappaB (IkappaB) degradation, and consequently the Ti-induced transcriptional activation of AP-1 and NF-kappaB. In a mouse calvarial osteolysis model, EGCG inhibited Ti particle-induced osteolysis in vivo by suppressing TNF-alpha expression and osteoclast formation. Therefore, EGCG may be a potential candidate compound for osteolysis prevention and treatment as well as aseptic loosening after total replacement arthroplasty.