Macrophages are generally thought to play a key role in the pathogenesis of aseptic loosening through initiating periprosthetic inflammation and pathological bone resorption. The aim of this study was to identify macrophage-derived factors that promote osteoclast differentiation and periprosthetic bone destruction. To achieve this, we examined the effects of 12 macrophage-derived factors that were identified by RNA-seq analysis of stimulated macrophages on osteoclast differentiation. Surprisingly, thymidine phosphorylase (TYMP) was found to trigger significant number of osteoclasts that exhibited resorbing activities on dentine slices. Functionally, TYMP knockdown reduced the number of osteoclasts in macrophages that had been stimulated with polyethylene debris. TYMP were detected in serum and synovial tissues of patients that had been diagnosed with aseptic loosening. Moreover, the administration of TYMP onto calvariae of mice induced pathological bone resorption that was accompanied by an excessive infiltration of inflammatory cells and osteoclasts. The RNA-seq for TYMP-induced-osteoclasts was then performed in an effort to understand action mode of TYMP. TYMP stimulation appeared to activate the tyrosine kinase FYN signaling associated with osteoclast formation. Oral administration of saracatinib, a FYN kinase inhibitor, significantly suppressed formation of bone osteolytic lesions in a polyethylene debris-induced osteolysis model. Our findings highlight a novel molecular target for therapeutic intervention in periprosthetic osteolysis.

中文翻译：

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靶向胸苷磷酸化酶作为假体周围骨溶解相关骨质流失的潜在疗法


通常认为巨噬细胞通过引发假体周围炎症和病理性骨吸收，在无菌性松动的发病机制中发挥关键作用。本研究的目的是确定促进破骨细胞分化和假体周围骨质破坏的巨噬细胞衍生因子。为了实现这一目标，我们检查了 12 种巨噬细胞衍生因子对破骨细胞分化的影响，这些因子是通过对受刺激的巨噬细胞进行 RNA 序列分析来鉴定的。令人惊讶的是，胸苷磷酸化酶（TYMP）被发现能够触发大量破骨细胞，这些破骨细胞在牙本质切片上表现出再吸收活性。从功能上讲，TYMP 敲低减少了受聚乙烯碎片刺激的巨噬细胞中破骨细胞的数量。在被诊断为无菌性松动的患者的血清和滑膜组织中检测到TYMP。此外，将 TYMP 施用到小鼠颅骨上会诱导病理性骨吸收，并伴有炎症细胞和破骨细胞的过度浸润。然后对 TYMP 诱导的破骨细胞进行 RNA 测序，以了解 TYMP 的作用模式。 TYMP 刺激似乎可以激活与破骨细胞形成相关的酪氨酸激酶 FYN 信号传导。在聚乙烯碎片诱导的骨质溶解模型中，口服 FYN 激酶抑制剂 saracatinib 可显着抑制骨溶骨性病变的形成。我们的研究结果强调了假体周围骨溶解治疗干预的新分子靶点。