Phosphatidyl Inositol 3-Kinase (PI3K)-Inhibitor CDZ173 protects against LPS-induced osteolysis
A major complication of a joint replacement is prosthesis loosening caused by inflammatory osteolysis, leading to the revision of the operation. This is due to the abnormal activation of osteoclast differentiation and function caused by periprosthetic infection. Therefore, targeting abnormally activ...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1021714/full |
| _version_ | 1828070236016869376 |
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| author | Zuoxing Wu Zuoxing Wu Zuoxing Wu Xuedong Li Xiaohui Chen Xiaohui Chen Xiaohui Chen Xuemei He Yu Chen Long Zhang Zan Li Mengyu Yang Guixin Yuan Baohong Shi Ning Chen Na Li Na Li Na Li Haotian Feng Mengyu Zhou Gang Rui Feng Xu Ren Xu Ren Xu Ren Xu Ren Xu |
| author_facet | Zuoxing Wu Zuoxing Wu Zuoxing Wu Xuedong Li Xiaohui Chen Xiaohui Chen Xiaohui Chen Xuemei He Yu Chen Long Zhang Zan Li Mengyu Yang Guixin Yuan Baohong Shi Ning Chen Na Li Na Li Na Li Haotian Feng Mengyu Zhou Gang Rui Feng Xu Ren Xu Ren Xu Ren Xu Ren Xu |
| author_sort | Zuoxing Wu |
| collection | DOAJ |
| description | A major complication of a joint replacement is prosthesis loosening caused by inflammatory osteolysis, leading to the revision of the operation. This is due to the abnormal activation of osteoclast differentiation and function caused by periprosthetic infection. Therefore, targeting abnormally activated osteoclasts is still effective for treating osteolytic inflammatory diseases. CDZ173 is a selective PI3K inhibitor widely used in autoimmune-related diseases and inflammatory diseases and is currently under clinical development. However, the role and mechanism of CDZ173 in osteoclast-related bone metabolism remain unclear. The possibility for treating aseptic prosthesis loosening brought on by inflammatory osteolysis illness can be assessed using an LPS-induced mouse cranial calcium osteolysis model. In this study, we report for the first time that CDZ173 has a protective effect on LPS-induced osteolysis. The data show that this protective effect is due to CDZ173 inhibiting the activation of osteoclasts in vivo. Meanwhile, our result demonstrated that CDZ173 had a significant inhibitory effect on RANKL-induced osteoclasts. Furthermore, using the hydroxyapatite resorption pit assay and podosol actin belt staining, respectively, the inhibitory impact of CDZ173 on bone resorption and osteoclast fusion of pre-OC was determined. In addition, staining with alkaline phosphatase (ALP) and alizarin red (AR) revealed that CDZ173 had no effect on osteoblast development in vitro. Lastly, CDZ173 inhibited the differentiation and function of osteoclasts by weakening the signal axis of PI3K-AKT/MAPK-NFATc1 in osteoclasts. In conclusion, our results highlight the potential pharmacological role of CDZ173 in preventing osteoclast-mediated inflammatory osteolysis and its potential clinical application. |
| first_indexed | 2024-04-11T00:34:42Z |
| format | Article |
| id | doaj.art-40170d2f452a48c699705cc55820cc75 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T00:34:42Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-40170d2f452a48c699705cc55820cc752023-01-06T23:21:06ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-01-011310.3389/fphar.2022.10217141021714Phosphatidyl Inositol 3-Kinase (PI3K)-Inhibitor CDZ173 protects against LPS-induced osteolysisZuoxing Wu0Zuoxing Wu1Zuoxing Wu2Xuedong Li3Xiaohui Chen4Xiaohui Chen5Xiaohui Chen6Xuemei He7Yu Chen8Long Zhang9Zan Li10Mengyu Yang11Guixin Yuan12Baohong Shi13Ning Chen14Na Li15Na Li16Na Li17Haotian Feng18Mengyu Zhou19Gang Rui20Feng Xu21Ren Xu22Ren Xu23Ren Xu24Ren Xu25Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaThe First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Medical Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, ChinaDepartment of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaThe First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, ChinaThe First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, ChinaThe First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, ChinaThe First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Sports Medicine, Xiangya Hospital, Central South University, Changsha, ChinaThe First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, ChinaThe First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, ChinaThe First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Endocrinology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, ChinaDepartment of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaThe First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, ChinaInner Mongolia Dairy Technology Research Institute Co. Ltd., Hohhot, ChinaDepartment of Dentistry, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaDepartment of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Subject Planning, Ninth People’s Hospital Shanghai, Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaThe First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, China0Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaA major complication of a joint replacement is prosthesis loosening caused by inflammatory osteolysis, leading to the revision of the operation. This is due to the abnormal activation of osteoclast differentiation and function caused by periprosthetic infection. Therefore, targeting abnormally activated osteoclasts is still effective for treating osteolytic inflammatory diseases. CDZ173 is a selective PI3K inhibitor widely used in autoimmune-related diseases and inflammatory diseases and is currently under clinical development. However, the role and mechanism of CDZ173 in osteoclast-related bone metabolism remain unclear. The possibility for treating aseptic prosthesis loosening brought on by inflammatory osteolysis illness can be assessed using an LPS-induced mouse cranial calcium osteolysis model. In this study, we report for the first time that CDZ173 has a protective effect on LPS-induced osteolysis. The data show that this protective effect is due to CDZ173 inhibiting the activation of osteoclasts in vivo. Meanwhile, our result demonstrated that CDZ173 had a significant inhibitory effect on RANKL-induced osteoclasts. Furthermore, using the hydroxyapatite resorption pit assay and podosol actin belt staining, respectively, the inhibitory impact of CDZ173 on bone resorption and osteoclast fusion of pre-OC was determined. In addition, staining with alkaline phosphatase (ALP) and alizarin red (AR) revealed that CDZ173 had no effect on osteoblast development in vitro. Lastly, CDZ173 inhibited the differentiation and function of osteoclasts by weakening the signal axis of PI3K-AKT/MAPK-NFATc1 in osteoclasts. In conclusion, our results highlight the potential pharmacological role of CDZ173 in preventing osteoclast-mediated inflammatory osteolysis and its potential clinical application.https://www.frontiersin.org/articles/10.3389/fphar.2022.1021714/fullOsteoclastCDZ173OsteolysisPI3KMAPK |
| spellingShingle | Zuoxing Wu Zuoxing Wu Zuoxing Wu Xuedong Li Xiaohui Chen Xiaohui Chen Xiaohui Chen Xuemei He Yu Chen Long Zhang Zan Li Mengyu Yang Guixin Yuan Baohong Shi Ning Chen Na Li Na Li Na Li Haotian Feng Mengyu Zhou Gang Rui Feng Xu Ren Xu Ren Xu Ren Xu Ren Xu Phosphatidyl Inositol 3-Kinase (PI3K)-Inhibitor CDZ173 protects against LPS-induced osteolysis Frontiers in Pharmacology Osteoclast CDZ173 Osteolysis PI3K MAPK |
| title | Phosphatidyl Inositol 3-Kinase (PI3K)-Inhibitor CDZ173 protects against LPS-induced osteolysis |
| title_full | Phosphatidyl Inositol 3-Kinase (PI3K)-Inhibitor CDZ173 protects against LPS-induced osteolysis |
| title_fullStr | Phosphatidyl Inositol 3-Kinase (PI3K)-Inhibitor CDZ173 protects against LPS-induced osteolysis |
| title_full_unstemmed | Phosphatidyl Inositol 3-Kinase (PI3K)-Inhibitor CDZ173 protects against LPS-induced osteolysis |
| title_short | Phosphatidyl Inositol 3-Kinase (PI3K)-Inhibitor CDZ173 protects against LPS-induced osteolysis |
| title_sort | phosphatidyl inositol 3 kinase pi3k inhibitor cdz173 protects against lps induced osteolysis |
| topic | Osteoclast CDZ173 Osteolysis PI3K MAPK |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1021714/full |
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