Rac1-dependent regulation of osteoclast and osteoblast differentiation by developmentally regulated GTP-binding 2
Abstract Multiple small GTPases play crucial roles in bone homeostasis by regulating the differentiation and function of bone cells, including osteoclasts and osteoblasts. Here, we investigated whether developmentally regulated GTP-binding protein 2 (Drg2), a subfamily of the GTPase superfamily, cou...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02338-7 |
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| _version_ | 1823863314674876416 |
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| author | Jung Ha Kim Semun Seong Kabsun Kim Inyoung Kim Jeong Woo Park Jeong-Tae Koh Nacksung Kim |
| author_facet | Jung Ha Kim Semun Seong Kabsun Kim Inyoung Kim Jeong Woo Park Jeong-Tae Koh Nacksung Kim |
| author_sort | Jung Ha Kim |
| collection | DOAJ |
| description | Abstract Multiple small GTPases play crucial roles in bone homeostasis by regulating the differentiation and function of bone cells, including osteoclasts and osteoblasts. Here, we investigated whether developmentally regulated GTP-binding protein 2 (Drg2), a subfamily of the GTPase superfamily, could affect bone mass by regulating osteoclast and osteoblast differentiation. Downregulation of Drg2 using siRNA in bone marrow-derived macrophages inhibited osteoclast differentiation and function and Rac1 activation in vitro. Comparatively, Drg2 downregulation in calvarial-derived osteoprogenitor cells enhanced osteoblast differentiation and function in vitro. Rac1 activation was also suppressed by Drg2 downregulation in osteoprogenitor cells. Both osteoclast and osteoblast differentiation regulated by Drg2 downregulation were restored by suppressing Rac1 activity. Drg2-deficient mice showed increased bone mass due to a dramatic reduction in osteoclast numbers without significantly affecting the number of osteoblasts. Furthermore, Drg2 downregulation strongly inhibited RANKL-induced bone loss in vivo. In summary, Drg2 contributes to bone homeostasis by regulating the differentiation and function of osteoclasts and osteoblasts through Rac1 activation. In particular, the effect of Drg2 on osteoclasts is strong enough to regulate bone mass in vivo; therefore, Drg2 has significant potential for use as a therapeutic target in bone loss-related diseases. |
| format | Article |
| id | doaj-art-e4fa1d8438d24ddf98a3c5abd4544f8d |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-e4fa1d8438d24ddf98a3c5abd4544f8d2025-02-09T12:12:35ZengNature Publishing GroupCell Death Discovery2058-77162025-02-0111111110.1038/s41420-025-02338-7Rac1-dependent regulation of osteoclast and osteoblast differentiation by developmentally regulated GTP-binding 2Jung Ha Kim0Semun Seong1Kabsun Kim2Inyoung Kim3Jeong Woo Park4Jeong-Tae Koh5Nacksung Kim6Department of Pharmacology, Chonnam National University Medical SchoolDepartment of Pharmacology, Chonnam National University Medical SchoolDepartment of Pharmacology, Chonnam National University Medical SchoolDepartment of Pharmacology, Chonnam National University Medical SchoolDepartment of Biological Sciences, University of UlsanHard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National UniversityDepartment of Pharmacology, Chonnam National University Medical SchoolAbstract Multiple small GTPases play crucial roles in bone homeostasis by regulating the differentiation and function of bone cells, including osteoclasts and osteoblasts. Here, we investigated whether developmentally regulated GTP-binding protein 2 (Drg2), a subfamily of the GTPase superfamily, could affect bone mass by regulating osteoclast and osteoblast differentiation. Downregulation of Drg2 using siRNA in bone marrow-derived macrophages inhibited osteoclast differentiation and function and Rac1 activation in vitro. Comparatively, Drg2 downregulation in calvarial-derived osteoprogenitor cells enhanced osteoblast differentiation and function in vitro. Rac1 activation was also suppressed by Drg2 downregulation in osteoprogenitor cells. Both osteoclast and osteoblast differentiation regulated by Drg2 downregulation were restored by suppressing Rac1 activity. Drg2-deficient mice showed increased bone mass due to a dramatic reduction in osteoclast numbers without significantly affecting the number of osteoblasts. Furthermore, Drg2 downregulation strongly inhibited RANKL-induced bone loss in vivo. In summary, Drg2 contributes to bone homeostasis by regulating the differentiation and function of osteoclasts and osteoblasts through Rac1 activation. In particular, the effect of Drg2 on osteoclasts is strong enough to regulate bone mass in vivo; therefore, Drg2 has significant potential for use as a therapeutic target in bone loss-related diseases.https://doi.org/10.1038/s41420-025-02338-7 |
| spellingShingle | Jung Ha Kim Semun Seong Kabsun Kim Inyoung Kim Jeong Woo Park Jeong-Tae Koh Nacksung Kim Rac1-dependent regulation of osteoclast and osteoblast differentiation by developmentally regulated GTP-binding 2 Cell Death Discovery |
| title | Rac1-dependent regulation of osteoclast and osteoblast differentiation by developmentally regulated GTP-binding 2 |
| title_full | Rac1-dependent regulation of osteoclast and osteoblast differentiation by developmentally regulated GTP-binding 2 |
| title_fullStr | Rac1-dependent regulation of osteoclast and osteoblast differentiation by developmentally regulated GTP-binding 2 |
| title_full_unstemmed | Rac1-dependent regulation of osteoclast and osteoblast differentiation by developmentally regulated GTP-binding 2 |
| title_short | Rac1-dependent regulation of osteoclast and osteoblast differentiation by developmentally regulated GTP-binding 2 |
| title_sort | rac1 dependent regulation of osteoclast and osteoblast differentiation by developmentally regulated gtp binding 2 |
| url | https://doi.org/10.1038/s41420-025-02338-7 |
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