Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Biomater Sci. 2020 Jun 7;8(11):3147-3163. doi: 10.1039/d0bm00147c. Epub 2020 May 4.
Aseptic loosening (AL) caused by wear particles released from implant surfaces is one of the main causes for the failure of artificial joints, which is initiated by macrophage inflammatory responses. Emerging evidence suggests that the member of a broad-complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) family as well as zinc finger and BTB domain-containing protein 20 (ZBTB20) can inhibit IκBα gene transcription, promote NF-κB activation, and initiate innate immune responses. The molecular mechanism(s) by which ZBTB20 contributes to titanium particle (TiP)-induced macrophage inflammatory responses and osteolysis has not been fully elucidated. Here, we showed that ZBTB20 increased either in the AL group's synovial membranes or in TiP-stimulated bone-marrow-derived macrophages (BMDMs) as compared to that in the control groups. Moreover, the knockdown of ZBTB20 led to the inhibition of proinflammatory factors induced by TiPs in BMDMs, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-β (IFN-β). Here, we also reported that the knockdown of ZBTB20 suppressed TiP-induced NF-κB activation and M1 polarization as well as stabilized the trans Golgi network (TGN) in BMDMs. The dual-luciferase reporter assay identified the binding between the IκBα promoter and ZBTB20, and IκBα knockdown could rescue the antiinflammatory effects induced by the ZBTB20 knockdown in BMDMs. Finally, we found that sh-ZBTB20 lentivirus injection could reduce TiP-induced osteolysis in mouse calvaria, inhibiting TiP-induced proinflammatory factors and loss of bone volume/total volume (BV/TV) as well as bone mineral density (BMD). These results suggest that ZBTB20 positively regulated NF-κB activation and M1 polarization as well as the production of TGN-derived tubular carriers in BMDMs, playing a positive role in macrophage activation and mouse cranial osteolysis induced by TiPs. It may be a potential therapeutic target for the prevention of aseptic loosening of prostheses.
无菌性松动（AL）是由植入物表面释放的磨损颗粒引起的，是人工关节失效的主要原因之一，其由巨噬细胞炎症反应引发。新出现的证据表明，广泛复合物、轨道、布里克-布拉克/痘病毒和锌指（BTB/POZ）家族成员以及锌指和 BTB 结构域包含蛋白 20（ZBTB20）可以抑制 IκBα 基因转录，促进 NF-κB 激活，并引发固有免疫反应。ZBTB20 促进钛颗粒（TiP）诱导的巨噬细胞炎症反应和骨溶解的分子机制尚未完全阐明。在这里，我们发现与对照组相比，AL 组的滑膜膜或 TiP 刺激的骨髓来源巨噬细胞（BMDM）中 ZBTB20 的表达增加。此外，ZBTB20 的敲低导致 BMDM 中由 TiP 诱导的促炎因子（如肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和干扰素-β（IFN-β））的抑制。在这里，我们还报告说，ZBTB20 的敲低抑制了 TiP 诱导的 NF-κB 激活和 M1 极化以及 BMDM 中转高尔基网络（TGN）的稳定。双荧光素酶报告基因检测鉴定了 IκBα 启动子与 ZBTB20 之间的结合，IκBα 的敲低可以挽救 ZBTB20 敲低在 BMDM 中诱导的抗炎作用。最后，我们发现 sh-ZBTB20 慢病毒注射可减少小鼠颅骨中的 TiP 诱导的骨溶解，抑制 TiP 诱导的促炎因子和骨体积/总体积（BV/TV）以及骨密度（BMD）的丧失。这些结果表明，ZBTB20 正向调节 NF-κB 激活和 M1 极化以及 BMDM 中转高尔基网络衍生的管状载体的产生，在 TiP 诱导的巨噬细胞激活和小鼠颅骨骨溶解中发挥积极作用。它可能是预防假体无菌性松动的潜在治疗靶点。
