BHLHE40 promotes osteoclastogenesis and abnormal bone resorption via c-Fos/NFATc1
Abstract Background Dysregulated osteoclast activity due to altered osteoclast differentiation causes multiple bone diseases. Osteoclasts are multinucleated giant cells derived from hematopoietic stem cells and play a major role in bone absorption. However, the mechanisms underlying the tight regula...
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| Format: | Article |
| Language: | English |
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BMC
2022-05-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-022-00813-7 |
| _version_ | 1811253566286856192 |
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| author | Yufeng Zhang Min Yang Sheng Zhang Zhiqiang Yang Yufan Zhu Yi Wang Zhe Chen Xuan Lv Zan Huang Yuanlong Xie Lin Cai |
| author_facet | Yufeng Zhang Min Yang Sheng Zhang Zhiqiang Yang Yufan Zhu Yi Wang Zhe Chen Xuan Lv Zan Huang Yuanlong Xie Lin Cai |
| author_sort | Yufeng Zhang |
| collection | DOAJ |
| description | Abstract Background Dysregulated osteoclast activity due to altered osteoclast differentiation causes multiple bone diseases. Osteoclasts are multinucleated giant cells derived from hematopoietic stem cells and play a major role in bone absorption. However, the mechanisms underlying the tight regulation of osteoclast differentiation in multiple pathophysiological status remain unknown. Results We showed that Bhlhe40 upregulation is tightly associated with osteoclast differentiation and osteoporosis. Functionally, Bhlhe40 promoted osteoclast differentiation in vitro, and Bhlhe40 deficiency led to increased bone mass and decreased osteoclast differentiation in vivo. Moreover, Bhlhe40 deficient mice resisted estrogen deficiency and aging-induced osteoporosis. Mechanism study showed that the increase in bone mass due to Bhlhe40 deficiency was a cell intrinsic defect in osteoclast differentiation in these mice. BHLHE40 upregulated the gene expression of Fos and Nfatc1 by directly binding to their promoter regions. Notably, inhibition of Fos/Nfatc1 abrogated the enhanced osteoclast differentiation induced by BHLHE40 overexpression. Conclusions Our research reveals a novel Bhlhe40/c-Fos/Nfatc1 axis involved in regulating osteoclastogenesis and shows that osteoporosis caused by estrogen deficiency and aging can be rescued by regulating Bhlhe40 in mice. This may help in the development of a new strategy for the treatment of osteoporosis. |
| first_indexed | 2024-04-12T16:54:01Z |
| format | Article |
| id | doaj.art-8f0abeefd45c4a4289c8cfd68578ed21 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-12T16:54:01Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-8f0abeefd45c4a4289c8cfd68578ed212022-12-22T03:24:19ZengBMCCell & Bioscience2045-37012022-05-0112112010.1186/s13578-022-00813-7BHLHE40 promotes osteoclastogenesis and abnormal bone resorption via c-Fos/NFATc1Yufeng Zhang0Min Yang1Sheng Zhang2Zhiqiang Yang3Yufan Zhu4Yi Wang5Zhe Chen6Xuan Lv7Zan Huang8Yuanlong Xie9Lin Cai10Department of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityCollege of Life Sciences, Wuhan UniversityDepartment of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityAbstract Background Dysregulated osteoclast activity due to altered osteoclast differentiation causes multiple bone diseases. Osteoclasts are multinucleated giant cells derived from hematopoietic stem cells and play a major role in bone absorption. However, the mechanisms underlying the tight regulation of osteoclast differentiation in multiple pathophysiological status remain unknown. Results We showed that Bhlhe40 upregulation is tightly associated with osteoclast differentiation and osteoporosis. Functionally, Bhlhe40 promoted osteoclast differentiation in vitro, and Bhlhe40 deficiency led to increased bone mass and decreased osteoclast differentiation in vivo. Moreover, Bhlhe40 deficient mice resisted estrogen deficiency and aging-induced osteoporosis. Mechanism study showed that the increase in bone mass due to Bhlhe40 deficiency was a cell intrinsic defect in osteoclast differentiation in these mice. BHLHE40 upregulated the gene expression of Fos and Nfatc1 by directly binding to their promoter regions. Notably, inhibition of Fos/Nfatc1 abrogated the enhanced osteoclast differentiation induced by BHLHE40 overexpression. Conclusions Our research reveals a novel Bhlhe40/c-Fos/Nfatc1 axis involved in regulating osteoclastogenesis and shows that osteoporosis caused by estrogen deficiency and aging can be rescued by regulating Bhlhe40 in mice. This may help in the development of a new strategy for the treatment of osteoporosis.https://doi.org/10.1186/s13578-022-00813-7BHLHE40NFATc1c-FosOsteoclastBone Resorption |
| spellingShingle | Yufeng Zhang Min Yang Sheng Zhang Zhiqiang Yang Yufan Zhu Yi Wang Zhe Chen Xuan Lv Zan Huang Yuanlong Xie Lin Cai BHLHE40 promotes osteoclastogenesis and abnormal bone resorption via c-Fos/NFATc1 Cell & Bioscience BHLHE40 NFATc1 c-Fos Osteoclast Bone Resorption |
| title | BHLHE40 promotes osteoclastogenesis and abnormal bone resorption via c-Fos/NFATc1 |
| title_full | BHLHE40 promotes osteoclastogenesis and abnormal bone resorption via c-Fos/NFATc1 |
| title_fullStr | BHLHE40 promotes osteoclastogenesis and abnormal bone resorption via c-Fos/NFATc1 |
| title_full_unstemmed | BHLHE40 promotes osteoclastogenesis and abnormal bone resorption via c-Fos/NFATc1 |
| title_short | BHLHE40 promotes osteoclastogenesis and abnormal bone resorption via c-Fos/NFATc1 |
| title_sort | bhlhe40 promotes osteoclastogenesis and abnormal bone resorption via c fos nfatc1 |
| topic | BHLHE40 NFATc1 c-Fos Osteoclast Bone Resorption |
| url | https://doi.org/10.1186/s13578-022-00813-7 |
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