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Abstract：
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.
摘要：
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理中起关键作用。这项研究的目的是鉴定促进破骨细胞分化和假体周围骨破坏的巨噬细胞衍生因子。为了实现这一点，我们研究了通过RNA-seq分析鉴定的12种巨噬细胞衍生因子对破骨细胞分化的影响.令人惊讶的是,发现胸苷磷酸化酶（TYMP）可触发大量破骨细胞，这些破骨细胞在牙本质切片上表现出吸收活性。功能上,TYMP敲除减少了用聚乙烯碎片刺激的巨噬细胞中破骨细胞的数量。在已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，在小鼠的颅骨上施用TYMP诱导病理性骨吸收，并伴有炎性细胞和破骨细胞的过度浸润。然后进行TYMP诱导的破骨细胞的RNA-seq以努力理解TYMP的作用模式。TYMP刺激似乎激活与破骨细胞形成相关的酪氨酸激酶FYN信号传导。口服给药saracatinib，FYN激酶抑制剂，在聚乙烯碎片诱导的骨溶解模型中，骨溶骨病变的形成受到显著抑制。我们的发现强调了一种用于治疗性干预假体周围骨溶解的新型分子靶标。
