机构：[1]Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China[2]Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
As wear particles-induced osteolysis still remains the leading cause of early implant loosening in endoprosthetic surgery, and promotion of osteoclastogenesis by wear particles has been confirmed to be responsible for osteolysis. Therapeutic agents targeting osteoclasts formation are considered for the treatment of wear particles-induced osteolysis. In the present study, we demonstrated for the first time that desferrioxamine (DFO), a powerful iron chelator, could significantly alleviate osteolysis in an ultrahigh-molecular-weight polyethylene (UHMWPE) particles-induced mice calvaria osteolysis model. Furthermore, DFO attenuated calvaria osteolysis by restraining enhanced inflammatory osteoclastogenesis induced by UHMWPE particles. Consistent with the in vivo results, we found DFO was also able to inhibit osteoclastogenesis in a dose-dependent manner in vitro, as evidenced by reduction of osteoclasts formation and suppression of osteoclast specific genes expression. In addition, DFO dampened osteoclasts differentiation and formation at early stage but not at late stage. Mechanistically, the reduction of osteoclastogenesis by DFO was due to increased heme oxygenase-1 (HO-1) expression, as decreased osteoclasts formation induced by DFO was significantly restored after HO-1 was silenced by siRNA, while HO-1 agonist COPP treatment enhanced DFO-induced osteoclastogenesis inhibition. In addition, blocking of p38 mitogen-activated protein kinase (p38MAPK) signaling pathway promoted DFO-induced HO-1 expression, implicating that p38 signaling pathway was involved in DFO-mediated HO-1 expression. Taken together, our results suggested that DFO inhibited UHMWPE particles-induced osteolysis by restraining inflammatory osteoclastogenesis through upregulation of HO-1 via p38MAPK pathway. Thus, DFO might be used as an innovative and safe therapeutic alternative for treating wear particles-induced aseptic loosening.
基金：
This work was supported by the National Natural
Science Foundation of China (Grant number. 81371958, 81572099, 81300713);
Shanghai Municipal Science and Technology Commission biomedicine technology
support project (Grant number. 13431900702); Innovation Program of Shanghai
Municipal Education Commision (Grant number. 14YZ044); Shanghai Sailing program (Grant number. 16YF1410100); Research project of Shanghai municipal
health and Family Planning Commission (Grant number. 201640105).
第一作者机构：[1]Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
共同第一作者：
通讯作者：
通讯机构：[*1]Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No.197, The Second Ruijin Road, Huangpu District, Ruijin 2nd Road, Shanghai 200025, China.
推荐引用方式(GB/T 7714)：
Hui Kang,Yufei Yan,Peng Jia,et al.Desferrioxamine reduces ultrahigh-molecular-weight polyethylene-induced osteolysis by restraining inflammatory osteoclastogenesis via heme oxygenase-1[J].CELL DEATH & DISEASE.2016,7(10):e2435.doi:10.1038/cddis.2016.339.
APA：
Hui Kang,Yufei Yan,Peng Jia,Kai Yang,Changjun Guo...&Lianfu Deng.(2016).Desferrioxamine reduces ultrahigh-molecular-weight polyethylene-induced osteolysis by restraining inflammatory osteoclastogenesis via heme oxygenase-1.CELL DEATH & DISEASE,7,(10)
MLA：
Hui Kang,et al."Desferrioxamine reduces ultrahigh-molecular-weight polyethylene-induced osteolysis by restraining inflammatory osteoclastogenesis via heme oxygenase-1".CELL DEATH & DISEASE 7..10(2016):e2435
生物学