SPHK Inhibitors and Zoledronic Acid Suppress Osteoclastogenesis and Wear Particle-Induced Osteolysis.
SPHK Inhibitors and Zoledronic Acid Suppress Osteoclastogenesis and Wear Particle-Induced Osteolysis.
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DOI：
10.3389/fphar.2021.794429
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发表时间：
2021
影响因子：
5.6
通讯作者：
Sheng P
中科院分区：
文献类型：
--
作者：
Gu M;Pan B;Chen W;Xu H;Wu X;Hu X;Zheng L;Ye Y;Meng Q;Xian G;Zhang Z;Sheng P
背景：磨损颗粒引起的炎性骨溶解是人工关节置换术后假体松动的主要原因，其防治难度较大。我们先前的研究证实，鞘氨醇激酶(SPHKs)是调节磨粒诱导的巨噬细胞炎症反应的重要介质。然而，目前尚不清楚SPHKs是否可以调节慢性炎症和减轻骨溶解。唑来膦酸(ZA)是一种含咪唑的双膦酸类化合物，可直接作用于破骨细胞，预防骨矿相关疾病。然而，SPHK抑制剂和ZA用于治疗假体周围骨溶解的效果尚不清楚。方法：应用抗酒石酸酸性磷酸酶(TRAP)染色检测无菌性松动患者和对照组界面膜的骨破坏情况。采用小鼠颅骨溶解模型，观察SPHK抑制剂和ZA对小鼠颅骨溶解的预防作用。通过显微CT扫描、免疫组织化学(IHC)和组织形态计量学分析来确定炎性骨溶解的变化。采用细胞计数试剂盒(CCK-8)检测不同药物浓度对细胞活力的影响。实时定量聚合酶链式反应(RT-qPCR)分析证实药物和钛处理后破骨细胞特异性基因的表达降低。用TRAP染色分析药物在体内和体外的破骨细胞形成和功能。通过RT-qPCR和组织免疫组化验证SPHKs/S1P-TRAF2-BECN1信号通路的作用。结果：在本研究中，我们发现SPHK抑制剂(ABC294640和FTY720)联合ZA可以降低体内炎症骨溶解的程度。然而，ABC294640和ZA在体外抑制破骨细胞分化和破骨细胞特异性基因。SPHKs通过上调SPHKs/S1P-TRAF2-BECN1的表达来调节磨粒诱导的炎性骨溶解。结论：磨损颗粒可通过上调SPHKs/S1P-TRAF2-BECN1和SPHK抑制剂/ZA在体外抑制破骨细胞生成，防止体内炎性骨溶解，从而诱导炎性骨溶解，提示SPHK抑制剂和ZA可作为防治假体松动的新视角和科学依据。
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.
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DOI：
10.1002/jbmr.3945
发表时间：
2020-04
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Shin B;Kupferman J;Schmidt E;Polleux F;Delany AM;Lee SK
通讯作者：
Lee SK
DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
9.7
作者：
Gallo J;Vaculova J;Goodman SB;Konttinen YT;Thyssen JP
通讯作者：
Thyssen JP
骨盆矢状解剖参数在强直性脊柱炎患者初次全髋关节置换术中的作用
影响因子：
3.5
作者：
Gu, Minghui;Zhang, Zhiqi;Liao, Weiming
通讯作者：
Liao, Weiming
影响因子：
4.1
作者：
McEvoy, A;Jeyam, M;Andrew, JG
通讯作者：
Andrew, JG