Blockade of XCL1/Lymphotactin Ameliorates Severity of Periprosthetic Osteolysis Triggered by Polyethylene-Particles
Blockade of XCL1/Lymphotactin Ameliorates Severity of Periprosthetic Osteolysis Triggered by Polyethylene-Particles
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DOI：
10.3389/fimmu.2020.01720
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发表时间：
2020-08-04
影响因子：
7.3
通讯作者：
Iwasaki, Norimasa
中科院分区：
文献类型：
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作者：
Tian, Yuan;Terkawi, Mohamad Alaa;Iwasaki, Norimasa
由骨科植入物磨损颗粒引起的假体周围骨溶解仍然是大多数患者关节置换术失败的主要原因。磨损碎片的释放导致慢性局部炎症反应，其典型特征是免疫细胞（包括巨噬细胞）的募集。来自活化巨噬细胞的细胞介质有利于破骨细胞骨吸收活性，导致种植体部位骨丢失和假体部件松动。新出现的证据表明，趋化因子及其受体参与了与无菌植入物松动相关的假体周围骨溶解的进展。在当前的研究中，我们研究了趋化因子C-motif-ligand-1 （XCL1）在磨损颗粒诱导的炎症性骨溶解发病机制中的潜在作用。XCL1及其受体在翻修全髋关节置换术患者的滑液和髋关节周围组织中表达明显。此外，采用超高分子量聚乙烯（UHMWPE）颗粒诱导的小鼠颅骨骨溶解模型，研究XCL1在炎性骨溶解发生中的作用。在植入颗粒后，小鼠颅骨单次注射重组XCL1，显示出比对照小鼠更大的骨溶解病变。相比之下，中和抗体阻断XCL1可显著减少UHMWPE颗粒诱导的骨侵蚀和骨吸收成熟破骨细胞的数量。与结果一致的是，xcl1浸泡海绵移植到颅骨上引起溶骨病变，同时炎症细胞和破骨细胞过度浸润。这些结果提示XCL1可能通过促进炎症细胞和骨吸收-破骨细胞的浸润参与假体周围骨溶解的发生。我们进一步的研究结果表明，在核因子κ b配体受体激活剂（RANKL）刺激下，将重组XCL1补充到培养的人单核细胞中，可以促进破骨细胞的发生和破骨细胞的骨吸收活性。此外，重组XCL1促进了人分化成骨细胞中炎症因子、破骨因子IL-6、IL-8、RANKL的表达。总之，这些结果提示XCL1在假体周围骨溶解和无菌性松动的发病机制中的潜在作用。我们的数据拓宽了对无菌假体松动发病机制的认识，并强调了治疗干预的新分子靶点。
Periprosthetic osteolysis induced by orthopedic implant-wear particles continues to be the leading cause of arthroplasty failure in majority of patients. Release of the wear debris results in a chronic local inflammatory response typified by the recruitment of immune cells, including macrophages. The cellular mediators derived from activated macrophages favor the osteoclast-bone resorbing activity resulting in bone loss at the site of implant and loosening of the prosthetic components. Emerging evidence suggests that chemokines and their receptors are involved in the progression of periprosthetic osteolysis associated with aseptic implant loosening. In the current study, we investigated the potential role of chemokine C-motif-ligand-1 (XCL1) in the pathogenesis of inflammatory osteolysis induced by wear particles. Expressions of XCL1 and its receptor XCR1 were evident in synovial fluids and tissues surrounding hip-implants of patients undergoing revision total hip arthroplasty. Furthermore, murine calvarial osteolysis model induced by ultra-high molecular weight polyethylene (UHMWPE) particles was used to study the role of XCL1 in the development of inflammatory osteolysis. Mice received single injection of recombinant XCL1 onto the calvariae after implantation of particles exhibited significantly greater osteolytic lesions than the control mice. In contrast, blockade of XCL1 by neutralizing antibody significantly reduced bone erosion and the number of bone-resorbing mature osteoclasts induced by UHMWPE particles. In consistence with the results, transplantation of XCL1-soaked sponge onto calvariae caused osteolytic lesions coincident with excessive infiltration of inflammatory cells and osteoclasts. These results suggested that XCL1 might be involved in the development of periprosthetic osteolysis through promoting infiltration of inflammatory cells and bone resorbing-osteoclasts. Our further results demonstrated that supplementing recombinant XCL1 to cultured human monocytes stimulated with the receptor activator of nuclear factor kappa-B ligand (RANKL) promoted osteoclastogenesis and the osteoclast-bone resorbing activity. Moreover, recombinant XCL1 promoted the expression of inflammatory and osteoclastogenic factors, including IL-6, IL-8, and RANKL in human differentiated osteoblasts. Together, these results suggested the potential role of XCL1 in the pathogenesis of periprosthetic osteolysis and aseptic loosening. Our data broaden knowledge of the pathogenesis of aseptic prosthesis loosening and highlight a novel molecular target for therapeutic intervention.