Betulinic Acid Protects From Bone Loss in Ovariectomized Mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 Pathways
Osteoclasts with elevated bone resorption are commonly present in postmenopausal osteoporosis, and other osteolytic pathologies. Therefore, suppressing osteoclast generation and function has been the main focus of osteoporosis treatment. Betulinic acid (BA) represents a triterpenoid mainly purified...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-07-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2020.01025/full |
| _version_ | 1828813762704965632 |
|---|---|
| author | Jiyong Wei Jiyong Wei Jiyong Wei Jiyong Wei Yicheng Li Qian Liu Qian Liu Yanni Lan Chengming Wei Kun Tian Kun Tian Kun Tian Liwei Wu Liwei Wu Liwei Wu Chunbo Lin Jiake Xu Jiake Xu Jinmin Zhao Jinmin Zhao Jinmin Zhao Yuan Yang Yuan Yang Yuan Yang |
| author_facet | Jiyong Wei Jiyong Wei Jiyong Wei Jiyong Wei Yicheng Li Qian Liu Qian Liu Yanni Lan Chengming Wei Kun Tian Kun Tian Kun Tian Liwei Wu Liwei Wu Liwei Wu Chunbo Lin Jiake Xu Jiake Xu Jinmin Zhao Jinmin Zhao Jinmin Zhao Yuan Yang Yuan Yang Yuan Yang |
| author_sort | Jiyong Wei |
| collection | DOAJ |
| description | Osteoclasts with elevated bone resorption are commonly present in postmenopausal osteoporosis, and other osteolytic pathologies. Therefore, suppressing osteoclast generation and function has been the main focus of osteoporosis treatment. Betulinic acid (BA) represents a triterpenoid mainly purified from the bark of Betulaceae. BA shows multiple biological activities, including antitumor and anti-HIV properties, but its effect on osteolytic conditions is unknown. Here, BA suppressed receptor activator of nuclear factor‐κB ligand (RANKL)‐associated osteoclastogenesis and bone resorptive function, as assessed by tartrate‐resistant acid phosphatase (TRAP) staining, fibrous actin ring generation, and hydroxyapatite resorption assays. Mechanistically, BA downregulated the expression of osteoclastic-specific genes. Western blot analysis revealed that BA significantly interrupted ERK, JNK and p38 MAPK activation as well as intracellular reactive oxygen species (ROS) production, thus altering c-Fos and NFATc1 activation. Corroborating the above findings in cell-based assays, BA prevented ovariectomy-associated bone loss in an animal model. In conclusion, these findings suggest that BA can inhibit osteoclast generation and function as well as the RANKL signaling pathway, and might be used for treating osteoclast-related osteoporosis. |
| first_indexed | 2024-12-12T10:09:33Z |
| format | Article |
| id | doaj.art-a04dd9d89fd24ec792619356ed412c78 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-12T10:09:33Z |
| publishDate | 2020-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-a04dd9d89fd24ec792619356ed412c782022-12-22T00:27:50ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-07-011110.3389/fphar.2020.01025532112Betulinic Acid Protects From Bone Loss in Ovariectomized Mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 PathwaysJiyong Wei0Jiyong Wei1Jiyong Wei2Jiyong Wei3Yicheng Li4Qian Liu5Qian Liu6Yanni Lan7Chengming Wei8Kun Tian9Kun Tian10Kun Tian11Liwei Wu12Liwei Wu13Liwei Wu14Chunbo Lin15Jiake Xu16Jiake Xu17Jinmin Zhao18Jinmin Zhao19Jinmin Zhao20Yuan Yang21Yuan Yang22Yuan Yang23Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaGuangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, ChinaDepartment of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, ChinaDepartment of Orthopedics, The First People’s Hospital of Nanning, Nanning, ChinaResearch Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaSchool of Biomedical Sciences, The University of Western Australia, Perth, WA, AustraliaDepartment of Pharmacy, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, ChinaResearch Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaGuangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, ChinaDepartment of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaGuangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, ChinaDepartment of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, ChinaOrthopaedics, Langdong Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaSchool of Biomedical Sciences, The University of Western Australia, Perth, WA, AustraliaResearch Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaGuangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, ChinaDepartment of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaGuangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, ChinaOrthopaedics, Langdong Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, ChinaOsteoclasts with elevated bone resorption are commonly present in postmenopausal osteoporosis, and other osteolytic pathologies. Therefore, suppressing osteoclast generation and function has been the main focus of osteoporosis treatment. Betulinic acid (BA) represents a triterpenoid mainly purified from the bark of Betulaceae. BA shows multiple biological activities, including antitumor and anti-HIV properties, but its effect on osteolytic conditions is unknown. Here, BA suppressed receptor activator of nuclear factor‐κB ligand (RANKL)‐associated osteoclastogenesis and bone resorptive function, as assessed by tartrate‐resistant acid phosphatase (TRAP) staining, fibrous actin ring generation, and hydroxyapatite resorption assays. Mechanistically, BA downregulated the expression of osteoclastic-specific genes. Western blot analysis revealed that BA significantly interrupted ERK, JNK and p38 MAPK activation as well as intracellular reactive oxygen species (ROS) production, thus altering c-Fos and NFATc1 activation. Corroborating the above findings in cell-based assays, BA prevented ovariectomy-associated bone loss in an animal model. In conclusion, these findings suggest that BA can inhibit osteoclast generation and function as well as the RANKL signaling pathway, and might be used for treating osteoclast-related osteoporosis.https://www.frontiersin.org/article/10.3389/fphar.2020.01025/fullbetulinic acidosteoclastreceptor activator of nuclear factor‐κB ligandosteoporosisMAPK |
| spellingShingle | Jiyong Wei Jiyong Wei Jiyong Wei Jiyong Wei Yicheng Li Qian Liu Qian Liu Yanni Lan Chengming Wei Kun Tian Kun Tian Kun Tian Liwei Wu Liwei Wu Liwei Wu Chunbo Lin Jiake Xu Jiake Xu Jinmin Zhao Jinmin Zhao Jinmin Zhao Yuan Yang Yuan Yang Yuan Yang Betulinic Acid Protects From Bone Loss in Ovariectomized Mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 Pathways Frontiers in Pharmacology betulinic acid osteoclast receptor activator of nuclear factor‐κB ligand osteoporosis MAPK |
| title | Betulinic Acid Protects From Bone Loss in Ovariectomized Mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 Pathways |
| title_full | Betulinic Acid Protects From Bone Loss in Ovariectomized Mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 Pathways |
| title_fullStr | Betulinic Acid Protects From Bone Loss in Ovariectomized Mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 Pathways |
| title_full_unstemmed | Betulinic Acid Protects From Bone Loss in Ovariectomized Mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 Pathways |
| title_short | Betulinic Acid Protects From Bone Loss in Ovariectomized Mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 Pathways |
| title_sort | betulinic acid protects from bone loss in ovariectomized mice and suppresses rankl associated osteoclastogenesis by inhibiting the mapk and nfatc1 pathways |
| topic | betulinic acid osteoclast receptor activator of nuclear factor‐κB ligand osteoporosis MAPK |
| url | https://www.frontiersin.org/article/10.3389/fphar.2020.01025/full |
| work_keys_str_mv | AT jiyongwei betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT jiyongwei betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT jiyongwei betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT jiyongwei betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT yichengli betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT qianliu betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT qianliu betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT yannilan betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT chengmingwei betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT kuntian betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT kuntian betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT kuntian betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT liweiwu betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT liweiwu betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT liweiwu betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT chunbolin betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT jiakexu betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT jiakexu betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT jinminzhao betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT jinminzhao betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT jinminzhao betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT yuanyang betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT yuanyang betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways AT yuanyang betulinicacidprotectsfrombonelossinovariectomizedmiceandsuppressesranklassociatedosteoclastogenesisbyinhibitingthemapkandnfatc1pathways |