Nam Ju-Suk, Sharma Ashish Ranjan, Jagga Supriya, Lee Dong-Hyun, Sharma Garima, Nguyen Lich Thi, Lee Yeon Hee, Chang Jun-Dong, Chakraborty Chiranjib, Lee Sang-Soo
Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
Department of Bio-informatics, School of Computer and Information Sciences, Galgotias University, Greater Noida, 203201, India.
J Biomed Mater Res A. 2017 Mar;105(3):912-926. doi: 10.1002/jbm.a.36004.
Periprosthetic osteolysis remains the leading obstacle for total joint replacements. Primarily, it was thought that aseptic loosening is mainly caused by macrophage mediated inflammatory process arising from production of wear debris. The role of osteoclasts and its sequential bone resorption ability has been extensively studied, but little is known about impaired osteogenesis during osteolysis. In the current study, we have tried to delineate the regulatory mechanism of osteogenic signals by Ti particles in osteoprogenitor cells as well its participatory role in wear debris induced osteolysis. Implantation of Ti particles on mice calvaria induced pro-inflammatory response, elevated expression of COX2 and reduced the expression of Osterix. Treatment of Ti particles to MC3T3 E-1 cells displayed decreased osteogenic activity including ALP activity, mineralization and mRNA levels several osteogenic genes. Moreover, the basal activity of WNT and BMP signaling pathways was suppressed in MC3T3 E-1 cells treated with Ti particles. As an early response to Ti particles, MC3T3 E-1 cells showed activation of ERK and JNK. Co-inhibition of ERK and JNK with their specific inhibitors resulted in partial recovery of WNT and BMP signaling activity as well as ALP activity and collagen synthesis. Finally, LiCl mediated activation of WNT signaling pathway demonstrated rescue of Ti particle facilitated suppression of Osterix expression in mice calvaria. Our results provide evidences that WNT signaling pathway is regulated by ERK, JNK, and BMP signaling pathway during wear debris induced inflammatory osteolysis and may be considered as suitable therapeutic targets for the treatment. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 912-926, 2017.
假体周围骨溶解仍然是全关节置换的主要障碍。最初，人们认为无菌性松动主要是由磨损颗粒产生引发的巨噬细胞介导的炎症过程所致。破骨细胞的作用及其连续的骨吸收能力已得到广泛研究，但对于骨溶解过程中骨生成受损情况却知之甚少。在本研究中，我们试图阐明钛颗粒在骨祖细胞中对成骨信号的调控机制及其在磨损颗粒诱导的骨溶解中的参与作用。在小鼠颅骨上植入钛颗粒会引发促炎反应，COX2表达升高，而Osterix表达降低。用钛颗粒处理MC3T3 E-1细胞后，其成骨活性降低，包括碱性磷酸酶（ALP）活性、矿化以及几种成骨基因的mRNA水平。此外，用钛颗粒处理的MC3T3 E-1细胞中WNT和BMP信号通路的基础活性受到抑制。作为对钛颗粒的早期反应，MC3T3 E-1细胞显示出ERK和JNK的激活。用其特异性抑制剂共同抑制ERK和JNK可导致WNT和BMP信号活性以及ALP活性和胶原蛋白合成部分恢复。最后，LiCl介导的WNT信号通路激活证明可挽救钛颗粒促进的小鼠颅骨中Osterix表达的抑制。我们的结果表明，在磨损颗粒诱导的炎性骨溶解过程中，WNT信号通路受ERK、JNK和BMP信号通路调控，可被视为合适的治疗靶点。© 2016威利期刊公司。《生物医学材料研究杂志》A部分：105A：912 - 926，2017年。
