Abstract
Background: Inflammatory osteolysis induced by wear particles is the major cause of prosthetic loosening after artificial joint replacement, and its prevention and treatment are difficult worldwide. Our previous study confirmed that sphingosine kinases (SPHKs) are important mediators regulating the wear particle-induced macrophage inflammatory response. However, it is unclear whether SPHKs can modulate chronic inflammation and alleviate osteolysis. Zoledronic acid (ZA), an imidazole-containing bisphosphonate, directly affects osteoclasts and prevents bone mineral-related diseases. However, the effects of SPHK inhibitors and ZA used to treat periprosthetic osteolysis are unknown. Methods: We applied tartrate-resistant acid phosphatase (TRAP) staining to evaluate bone destruction in the interface membranes of patients with aseptic loosening and a control group. A murine calvarial osteolysis model was used to examine the preventative effect of SPHK inhibitors and ZA on osteolysis. Micro-CT scanning, immunohistochemistry (IHC), and histomorphometric analysis were conducted to determine the variations in inflammatory osteolysis. The effects of different drug concentrations on cell viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to confirm the reduced expression of osteoclast-specific genes after drug and titanium treatment. The osteoclast formation and functions of the drugs were analyzed using TRAP staining in vivo and in vitro. The effect of SPHKs/S1P-TRAF2-BECN1 signaling pathways was verified via RT-qPCR and tissue IHC. Results: In this study, we found that SPHK inhibitors (ABC294640 and FTY720) combined with ZA decreased the degree of inflammatory osteolysis in vivo. However, ABC294640 and ZA suppressed osteoclast differentiation and osteoclast-specific genes in vitro. SPHKs regulate the inflammatory osteolysis induced by wear particles by increasing the expression of SPHKs/S1P-TRAF2-BECN1. Conclusion: Our study revealed that wear particles could induce inflammatory osteolysis by upregulating SPHKs/S1P-TRAF2-BECN1 and SPHK inhibitors/ZA inhibit osteoclastogenesis in vitro and prevent inflammatory osteolysis in vivo, suggesting that SPHK inhibitors and ZA can be a new perspective and scientific basis for the prevention and treatment of prosthesis loosening.
Highlights
Aseptic prosthesis loosening (APL) is one of the most common complications after artificial joint replacement and is the most critical cause of prosthesis (Learmonth et al, 2007)
Zoledronic acid (ZA) and sphingosine kinases (SPHKs) inhibitors (FTY720/ABC294640) reduce inflammatory osteolysis induced by wear particles
After the intraperitoneal injection of ABC294640, FTY720, and ZA, upregulation of the inflammatory factors stimulated by Ti particles was inhibited (Figures 4B,D). These results showed that SPHK inhibitors (ABC294640/FTY720) and ZA significantly reduced the TNFα and IL-6 inflammatory cytokines in inflammatory osteolysis induced by wear particles
Summary
Aseptic prosthesis loosening (APL) is one of the most common complications after artificial joint replacement and is the most critical cause of prosthesis (Learmonth et al, 2007). Primarily titanium (Ti) particles, stimulate macrophages and other cells to release cytokines, chemokines, and other pro-inflammatory substances (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]), which allow chronic inflammation to further induce osteoclast (OC) resorption and inhibit bone formation (Mbalaviele et al, 2017). Our previous study confirmed that sphingosine kinases (SPHKs) are important mediators regulating the wear particle-induced macrophage inflammatory response It is unclear whether SPHKs can modulate chronic inflammation and alleviate osteolysis. The effects of SPHK inhibitors and ZA used to treat periprosthetic osteolysis are unknown
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