Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Department of Orthopaedics, Changshu Hospital Affiliated to Soochow University, First People's Hospital of Changshu City, Changshu, China.
J Nanobiotechnology. 2022 Mar 19;20(1):148. doi: 10.1186/s12951-022-01351-7.
Wear particle-induced periprosthetic osteolysis (PPO) have become a major reason of joint arthroplasty failure and secondary surgery following joint arthroplasty and thus pose a severe threat to global public health. Therefore, determining how to effectively suppress particle-induced PPO has become an urgent problem. The pathological mechanism involved in the PPO signaling cascade is still unclear. Recently, the interaction between osteogenic inhibition and wear particles at the implant biological interface, which has received increasing attention, has been revealed as an important factor in pathological process. Additionally, Hedgehog (Hh)-Gli1 is a crucial signaling cascade which was regulated by multiple factors in numerous physiological and pathological process. It was revealed to exert a crucial part during embryonic bone development and metabolism. However, whether Hh-Gli1 is involved in wear particle-induced osteogenic inhibition in PPO remains unknown. Our present study explored the mechanism by which the Hh-Gli1 signaling cascade regulates titanium (Ti) nanoparticle-induced osteolysis. We found that Hh-Gli1 signaling was dramatically downregulated upon Ti particle treatment. Mechanistically, glycogen synthesis kinase 3β (GSK-3β) activation was significantly increased in Ti particle-induced osteogenic inhibition via changes in GSK-3β phosphorylation level and was found to participate in the posttranslational modification and degradation of the key transcription factor Gli1, thus decreasing the accumulation of Gli1 and its translocation from the cytoplasm to the nucleus. Collectively, these findings suggest that the Hh-Gli1 signaling cascade utilizes a GSK3β-mediated mechanism and may serve as a rational new therapeutic target against nanoparticle-induced PPO.
磨屑诱导的假体周围骨溶解（PPO）已成为关节置换术后失败和继发性手术的主要原因，因此对全球公众健康构成严重威胁。因此，确定如何有效抑制颗粒诱导的 PPO 已成为一个紧迫的问题。PPO 信号级联涉及的病理机制尚不清楚。最近，在植入物生物界面，骨生成抑制与磨屑之间的相互作用受到越来越多的关注，已被揭示为病理过程中的一个重要因素。此外，Hedgehog（Hh）-Gli1 是一个关键的信号级联，它在许多生理和病理过程中受到多种因素的调节。它被揭示在胚胎骨发育和代谢过程中发挥重要作用。然而，Hh-Gli1 是否参与 PPO 中的磨屑诱导的成骨抑制尚不清楚。本研究探讨了 Hh-Gli1 信号级联调节钛（Ti）纳米颗粒诱导的溶骨性的机制。研究发现，Ti 颗粒处理后 Hh-Gli1 信号显著下调。在机制上，通过改变 GSK-3β 磷酸化水平，Ti 颗粒诱导的成骨抑制中糖原合成激酶 3β（GSK-3β）的激活显著增加，并且参与了关键转录因子 Gli1 的翻译后修饰和降解，从而减少 Gli1 的积累及其从细胞质向细胞核的易位。总之，这些发现表明 Hh-Gli1 信号级联利用 GSK3β 介导的机制，可能成为针对纳米颗粒诱导的 PPO 的合理的新治疗靶点。
