Metformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype
Abstract Background Implant failure remains a major obstacle to successful treatment via TJA. Periprosthetic osteolysis and aseptic loosening are considered as proof of wear debris-induced disruption of local regulatory mechanisms related to excessive bone resorption associated with osteolysis and t...
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BioMed Central
2018-05-01
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| Series: | Molecular Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s10020-018-0013-x |
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doaj-art-041b53060be14955943e570b3805dc972018-08-16T00:41:14ZengBioMed CentralMolecular Medicine1076-15511528-36582018-05-0124111210.1186/s10020-018-0013-xMetformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotypeZhao Yan0Xiaoxi Tian1Jinyu Zhu2Zifan Lu3Lifeng Yu4Dawei Zhang5Yanwu Liu6Chongfei Yang7Qingsheng Zhu8Xiaorui Cao9PLA Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical UniversityEmergency department of Tangdu Hospital, Fourth Military Medical UniversityPLA Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical UniversityPLA Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical UniversityPLA Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical UniversityPLA Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical UniversityPLA Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical UniversityPLA Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical UniversityPLA Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical UniversityAbstract Background Implant failure remains a major obstacle to successful treatment via TJA. Periprosthetic osteolysis and aseptic loosening are considered as proof of wear debris-induced disruption of local regulatory mechanisms related to excessive bone resorption associated with osteolysis and the damage at the bone-prosthesis interface. Therefore, there is an immediate need to explore strategies for limiting and curing periprosthetic osteolysis and aseptic loosening. Methods We analyzed the in vitro cytokine production by primary mouse bone marrow macrophages (BMMs) that were exposed to ultra-high molecular weight polyethylene (UHMWPE) particles and treated with metformin at different concentrations with or without 5-aminoimidazole-4-carboxamide ribonucleoside to activate or inhibit AMPK. A mouse calvarial model was used to examine the in vivo effects of metformin on UHMWPE particle-induced osteolysis. Results With particles, primary mouse BMMs secreted more pro-inflammatory cytokines tumor necrosis factor-α and interleukin (IL)-6. Treatment with metformin inhibited these variations and promoted the release of cytokine IL-10 with anti-inflammatory capability. In vivo, metformin reduced the production of pro-inflammatory cytokines, osteoclastogenesis, and osteolysis, increasing IL-10 production. Metformin also promoted the polarization of macrophages to an anti-inflammatory phenotype in vivo via AMPK activation. Discussion A crucial point in limiting and correcting the periprosthetic osteolysis and aseptic loosening is the inhibition of inflammatory factor production and osteoclast activation induced by activated macrophages. The ability of metformin to attenuate osteolysis induced in mouse calvaria by the particles was related to a reduction in osteoclast number and polarization of macrophages to an anti-inflammatory functional phenotype. Conclusions Metformin could limit the osteolysis induced by implant debris. Therefore, we hypothesized that metformin could be a potential drug for osteolysis induced by implant debris.http://link.springer.com/article/10.1186/s10020-018-0013-xInflammationOsteoclastsAMPKMacrophageOsteolysis |
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| language |
English |
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Article |
| author |
Zhao Yan Xiaoxi Tian Jinyu Zhu Zifan Lu Lifeng Yu Dawei Zhang Yanwu Liu Chongfei Yang Qingsheng Zhu Xiaorui Cao |
| spellingShingle |
Zhao Yan Xiaoxi Tian Jinyu Zhu Zifan Lu Lifeng Yu Dawei Zhang Yanwu Liu Chongfei Yang Qingsheng Zhu Xiaorui Cao Metformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype Molecular Medicine Inflammation Osteoclasts AMPK Macrophage Osteolysis |
| author_facet |
Zhao Yan Xiaoxi Tian Jinyu Zhu Zifan Lu Lifeng Yu Dawei Zhang Yanwu Liu Chongfei Yang Qingsheng Zhu Xiaorui Cao |
| author_sort |
Zhao Yan |
| title |
Metformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype |
| title_short |
Metformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype |
| title_full |
Metformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype |
| title_fullStr |
Metformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype |
| title_full_unstemmed |
Metformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype |
| title_sort |
metformin suppresses uhmwpe particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype |
| publisher |
BioMed Central |
| series |
Molecular Medicine |
| issn |
1076-1551 1528-3658 |
| publishDate |
2018-05-01 |
| description |
Abstract Background Implant failure remains a major obstacle to successful treatment via TJA. Periprosthetic osteolysis and aseptic loosening are considered as proof of wear debris-induced disruption of local regulatory mechanisms related to excessive bone resorption associated with osteolysis and the damage at the bone-prosthesis interface. Therefore, there is an immediate need to explore strategies for limiting and curing periprosthetic osteolysis and aseptic loosening. Methods We analyzed the in vitro cytokine production by primary mouse bone marrow macrophages (BMMs) that were exposed to ultra-high molecular weight polyethylene (UHMWPE) particles and treated with metformin at different concentrations with or without 5-aminoimidazole-4-carboxamide ribonucleoside to activate or inhibit AMPK. A mouse calvarial model was used to examine the in vivo effects of metformin on UHMWPE particle-induced osteolysis. Results With particles, primary mouse BMMs secreted more pro-inflammatory cytokines tumor necrosis factor-α and interleukin (IL)-6. Treatment with metformin inhibited these variations and promoted the release of cytokine IL-10 with anti-inflammatory capability. In vivo, metformin reduced the production of pro-inflammatory cytokines, osteoclastogenesis, and osteolysis, increasing IL-10 production. Metformin also promoted the polarization of macrophages to an anti-inflammatory phenotype in vivo via AMPK activation. Discussion A crucial point in limiting and correcting the periprosthetic osteolysis and aseptic loosening is the inhibition of inflammatory factor production and osteoclast activation induced by activated macrophages. The ability of metformin to attenuate osteolysis induced in mouse calvaria by the particles was related to a reduction in osteoclast number and polarization of macrophages to an anti-inflammatory functional phenotype. Conclusions Metformin could limit the osteolysis induced by implant debris. Therefore, we hypothesized that metformin could be a potential drug for osteolysis induced by implant debris. |
| topic |
Inflammation Osteoclasts AMPK Macrophage Osteolysis |
| url |
http://link.springer.com/article/10.1186/s10020-018-0013-x |
| _version_ |
1612696898301329408 |