No abstract

Zinc (Zn), an essential trace element, can stimulate bone formation and inhibit osteoclastic bone resorption, which controls the growth and maintenance of bone. However, the effect of Zn supplementation on tricalcium phosphate (TCP) wear particles‐induced osteolysis remains unknown. Here, we doped Zn into TCP particles (ZnTCP), and explore the protective effects of Zn on TCP particles‐induced osteolysis in vivo. TCP particles and ZnTCP particles were embedded under the periosteum around the middle suture of the mouse calvaria. After 2 weeks, blood, the periosteal tissue, and the calvaria were collected to determine serum levels of Zn and osteocalcin, pro‐inflammatory cytokines, bone biochemical markers, osteoclastogenesis and bone resorption area, and to explain its mechanism. Data revealed that Zn significantly prevented TCP particles‐induced osteoclastogenesis and bone loss, and increased bone turnover. The Zn supplement remarkably suppressed the release of pro‐inflammatory cytokines including tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, and IL‐6. Immunoblotting demonstrated that Zn alleviated expression levels of ER stress‐related proteins such as glucose‐regulated protein 78 (GRP78), PKR‐like ER kinase (PERK), phospho‐PERK (p‐PERK), eukaryotic initiation factor 2α (eIF2α), phospho‐eIF2α (p‐eIF2α), activating transcription factor 4 (ATF4), inositol‐requiring enzyme 1α (IRE1‐α) and transcription factor X‐box binding protein spliced (XBP1s), leading to decreasing the ratios of p‐PERK/PERK and p‐eIF2α/eIF2α. Taken together, Zn supplementation strongly prevents TCP particles‐induced periprosthetic osteolysis via inhibition of the ER stress pathway, and it may be a novel therapeutic approach for the treatment of aseptic prosthesis loosening.

Bisphenol S (BPS), a safer alternative to bisphenol A, is commonly used as a plasticizer to manufacture various food-packaging materials. The accumulated BPS inhibits osteoblastic bone formation and promotes osteoclastogenesis, thereby accelerating remarkable bone destruction, but it is unclear whether BPS affects osteocytes, comprising over 95% of all bone cells. This study aimed to investigate the biological effect of BPS on osteocytes in vitro, as well as the detailed mechanism. Results showed that BPS (200, 400 μmol/L) exposure caused dose-dependently cell death of osteocytes MLO-Y4, and increased cell apoptosis. BPS induced loss of mitochondrial membrane potential (MMP) and mitochondria impairment. Furthermore, BPS upregulated expressions of mitophagy-related proteins including microtubule-associated protein light chain 3 (LC-3) II and PTEN-induced putative kinase (PINK) 1, accompanied by elevation of autophagy flux and the accumulation of acidic vacuoles; whereas p62 level was downregulated after BPS treatment. Additionally, BPS triggered the production of intracellular reactive oxygen species (ROS) and mitochondrial ROS (mtROS), while it decreased expression levels of nuclear factor E2-related factor 2 (Nrf2) and quinone oxidoreductase 1 (NQO1). The specific mtROS scavenger Mito-TEMPO reversed cell apoptosis and mitophagy, suggesting that mtROS contributes to BPS exposure-induced apoptosis and mitophagy in MLO-Y4 cells. Our data first provide novel evidence that apoptosis and mitophagy as cellular mechanisms for the toxic effect of BPS on osteocytes, thereby helping our understanding of the potential role of osteocytes in the adverse effect of BPS and its analogs on bone growth, and supporting strategies targeting bone destruction caused by BPS.