Pharmacological Intervention with 4-Phenylbutyrate Ameliorates TiAl6V4 Nanoparticles-Induced Inflammatory Osteolysis by Promoting Macrophage Apoptosis.

Abstract

Macrophage apoptosis, along with inflammation in the interface membrane, has been demonstrated to be significant in the pathogenesis and development of particle-induced periprosthetic osteolysis and aseptic loosening. Additionally, the apoptosis of macrophages is considered an indicator of the resolution phase of inflammation and the transition to normal tissue healing. Therefore, targeting macrophages presents a promising strategy for both the prevention and therapeutic management of periprosthetic osteolysis. In this study, we explored the therapeutic potential of chemical chaperone 4-phenylbutyrate (4-PBA) as a pharmacological intervention aimed at modulating macrophage behaviors, particularly focusing on the processes of apoptosis, inflammation, and osteoclastogenesis in a murine model of TiAl6V4 nanoparticle (TiNP)-induced osteolysis. The results derived from in vivo studies conducted on the murine model provide compelling evidence that TiNPs could trigger osteolysis, activate inflammatory cell infiltration, and promote the differentiation of osteoclasts, accompanied by a notable rise in apoptosis at the osteolytic interface periosteum. The severity of TiNP-induced osteolysis, chaotic bone morphology, extensive bone erosion and destruction, occurrence of infiltrating inflammatory cells, and quantity of osteoclasts were attenuated following co-intervention with 4-PBA. Furthermore, the levels of apoptosis, in conjunction with apoptosis-regulated proteins Bcl-2 and Bax, were accentuated following 4-PBA co-intervention, indicating that the TiNP-induced osteolytic interface periosteum environment exhibited a greater propensity for apoptosis due to the pharmacological intervention of 4-PBA. Notably, the use of 4-PBA as a standalone treatment demonstrated comparatively low levels of toxicity and was deemed to be experimentally safe in mice. These findings indicated that 4-PBA may ameliorate the severity of particle-induced osteolysis by inhibiting the inflammatory response and promoting macrophage apoptosis in a manner that may be beneficial for therapeutic strategies. Thus, pharmacological intervention with 4-PBA appears to be a viable option for addressing osteolysis and aseptic loosening resulting from exposure to wear particles, combining efficacy in promoting apoptosis with a favorable safety profile.