Journal
CELL AND TISSUE RESEARCH
Volume 363, Issue 2, Pages 427-447Publisher
SPRINGER
DOI: 10.1007/s00441-015-2205-9
Keywords
Periprosthetic inflammatory osteolysis; Endoplasmic reticulum stress; Aseptic loosening; Wear particles; Inflammatory signaling pathways; Osteoclastogenesis; Human; Mouse
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Funding
- Natural Science Foundation of Jiangsu Province, China [BK2012776]
- Clinical Science projects of Jiangsu Province, China [2012002]
- Science and Technology Projects of Nanjing [201303039]
- Technological Innovation Projects of Nanjing Military Region [MS055]
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Aseptic loosening secondary to periprosthetic inflammatory osteolysis results from the biological response to wear particles and is a leading cause of arthroplasty failure. The origin of this inflammatory response remains unclear. We aim to validate the definite link between endoplasmic reticulum (ER) stress and particle-induced inflammatory signaling pathways in periprosthetic osteolysis. We examine the histopathologic changes of osteolysis and the expression of specific biomarkers for ER-stress-mediated inflammatory signaling pathways (IRE1 alpha, GRP78/Bip, c-Fos, NF-kappa B, ROS and Ca2+). Moreover, pro-inflammatory cytokines (TNF-alpha, IL-1 beta and IL-6) and osteoclastogenic molecules (VEGF, OPG, RANKL and M-CSF) were assessed in clinical interface membranes and murine periosteum tissues. We found wear particles to be capable of inducing ER stress in macrophages within clinical osteolytic interface membranes and murine osteolytic periosteum tissues and to be associated with the inflammatory response and osteoclastogenesis. Blocking ER stress with sodium 4-phenylbutyrate (4-PBA) results in a dramatic amelioration of particle-induced osteolysis and a significant reduction of ER-stress intensity. Simultaneously, this ER-stress blocker also lessens inflammatory cell infiltration, diminishes the capability of osteoclastogenesis and reduces the inflammatory response by lowering IRE1 alpha, GRP78/Bip, c-Fos, NF-kappa B, ROS and Ca2+ levels. Thus, ER stress plays an important role in particle-induced inflammatory osteolysis and osteoclastogenic reactions. The pharmacological targeting of ER-stress-mediated inflammatory signaling pathways might be an appealing approach for alleviating or preventing particle-induced osteolysis in at-risk patients.
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