Sodium 4-phenylbutyrate ameliorates particles-induced inflammatory osteolysis by promoting macrophage apoptosis and inhibiting inflammatory and osteoclastogenic reactions

Macrophages represent both the ‘initiators’ and ‘amplifiers’ of the pathogenetic cascade in inflammatory osteolysis. In this study, we investigated the therapeutic potential of ER-stress protector (PBA) on the inflammatory, osteoclastogenic and apoptotic reactions in cultured macrophages and osteolytic periosteum in particles-induced osteolysis (PIO) animal models. The results demonstrated that apoptosis-related markers, inflammation, and osteoclastogenesis were significantly up-regulated in particles-treated macrophages and osteolytic periosteum tissues. ER-stress protector down-regulated ER chaperone (IRE, Bip, CHOP), and ameliorated particles-induced osteolysis by promoting macrophage apoptosis and inhibiting the inflammatory reactions and osteoclastogenesis. During the apoptotic process, apoptotic regulators, JNK, the mitochondrial and death receptor pathways were all involved in PBA–induced macrophages apoptosis, while the ER stress pathway was not. More importantly, PBA treatment alone was of relative low toxicity and experimental tested safeness in PIO mice. Since the ER chaperone BiP migrates out of the ER into the nucleus (intracellular protein) and to the cell surface (extracellular protein). Thus, BiP conforms to the definition of a true moonlighting protein with two quite distinct roles. Besides the function that focused on preserving or restoring ER function, the BiP has also been implicated in exerting functions that are of immunologic importance, and the discovery of cell surface BiP makes it an innovative concept in biological therapy for inflammatory diseases. Therefore, future studies will need to address the many open questions about the physiological significance of the ER and Bip to improve the overall understanding of how these diseases develop and indicate how they might be treated with pharmacological interventions that modulate ER or Bip on inflammatory diseases.