SHIP1 Activator AQX-1125 Regulates Osteogenesis and Osteoclastogenesis Through PI3K/Akt and NF-κb Signaling
With the worldwide aging population, the prevalence of osteoporosis is on the rise, particularly the number of postmenopausal women with the condition. However, the various adverse side effects associated with the currently available treatment options underscore the need to develop novel therapies....
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.826023/full |
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| author | Xudong Xie Xudong Xie Liangcong Hu Liangcong Hu Bobin Mi Bobin Mi Adriana C. Panayi Hang Xue Hang Xue Yiqiang Hu Yiqiang Hu Guodong Liu Lang Chen Lang Chen Chenchen Yan Chenchen Yan Kangkang Zha Kangkang Zha Ze Lin Wu Zhou Wu Zhou Fei Gao Fei Gao Guohui Liu Guohui Liu |
| author_facet | Xudong Xie Xudong Xie Liangcong Hu Liangcong Hu Bobin Mi Bobin Mi Adriana C. Panayi Hang Xue Hang Xue Yiqiang Hu Yiqiang Hu Guodong Liu Lang Chen Lang Chen Chenchen Yan Chenchen Yan Kangkang Zha Kangkang Zha Ze Lin Wu Zhou Wu Zhou Fei Gao Fei Gao Guohui Liu Guohui Liu |
| author_sort | Xudong Xie |
| collection | DOAJ |
| description | With the worldwide aging population, the prevalence of osteoporosis is on the rise, particularly the number of postmenopausal women with the condition. However, the various adverse side effects associated with the currently available treatment options underscore the need to develop novel therapies. In this study, we investigated the use of AQX-1125, a novel clinical-stage activator of inositol phosphatase-1 (SHIP1), in ovariectomized (OVX) mice, identifying a protective role. We then found that the effect was likely due to increased osteogenesis and mineralization and decreased osteoclastogenesis caused by AQX-1125 in a time- and dose-dependent manner. The effect against OVX-induced bone loss was identified to be SHIP1-dependent as pretreatment of BMSCs and BMMs with SHIP1 RNAi could greatly diminish the osteoprotective effects. Furthermore, SHIP1 RNAi administration in vivo induced significant bone loss and decreased bone mass. Mechanistically, AQX-1125 upregulated the expression level and activity of SHIP1, followed upregulating the phosphorylation levels of PI3K and Akt to promote osteoblast-related gene expressions, including Alp, cbfa1, Col1a1, and osteocalcin (OCN). NF-κB signaling was also inhibited through suppression of the phosphorylation of IκBα and P65 induced by RANKL, resulting in diminished osteoclastogenesis. Taken together, our results demonstrate that AQX-1125 may be a promising candidate for preventing and treating bone loss. |
| first_indexed | 2024-04-13T02:33:44Z |
| format | Article |
| id | doaj.art-27c970b1d6fd429e97148acb2d29e68e |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-13T02:33:44Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-27c970b1d6fd429e97148acb2d29e68e2022-12-22T03:06:27ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-04-011010.3389/fcell.2022.826023826023SHIP1 Activator AQX-1125 Regulates Osteogenesis and Osteoclastogenesis Through PI3K/Akt and NF-κb SignalingXudong Xie0Xudong Xie1Liangcong Hu2Liangcong Hu3Bobin Mi4Bobin Mi5Adriana C. Panayi6Hang Xue7Hang Xue8Yiqiang Hu9Yiqiang Hu10Guodong Liu11Lang Chen12Lang Chen13Chenchen Yan14Chenchen Yan15Kangkang Zha16Kangkang Zha17Ze Lin18Wu Zhou19Wu Zhou20Fei Gao21Fei Gao22Guohui Liu23Guohui Liu24Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaDivision of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United StatesDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaMedical Center of Trauma and War Injuries, Daping Hospital, Army Medical University, Chongqing, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, ChinaWith the worldwide aging population, the prevalence of osteoporosis is on the rise, particularly the number of postmenopausal women with the condition. However, the various adverse side effects associated with the currently available treatment options underscore the need to develop novel therapies. In this study, we investigated the use of AQX-1125, a novel clinical-stage activator of inositol phosphatase-1 (SHIP1), in ovariectomized (OVX) mice, identifying a protective role. We then found that the effect was likely due to increased osteogenesis and mineralization and decreased osteoclastogenesis caused by AQX-1125 in a time- and dose-dependent manner. The effect against OVX-induced bone loss was identified to be SHIP1-dependent as pretreatment of BMSCs and BMMs with SHIP1 RNAi could greatly diminish the osteoprotective effects. Furthermore, SHIP1 RNAi administration in vivo induced significant bone loss and decreased bone mass. Mechanistically, AQX-1125 upregulated the expression level and activity of SHIP1, followed upregulating the phosphorylation levels of PI3K and Akt to promote osteoblast-related gene expressions, including Alp, cbfa1, Col1a1, and osteocalcin (OCN). NF-κB signaling was also inhibited through suppression of the phosphorylation of IκBα and P65 induced by RANKL, resulting in diminished osteoclastogenesis. Taken together, our results demonstrate that AQX-1125 may be a promising candidate for preventing and treating bone loss.https://www.frontiersin.org/articles/10.3389/fcell.2022.826023/fullAQX-1125SHIP1bone lossosteoblastosteoclast |
| spellingShingle | Xudong Xie Xudong Xie Liangcong Hu Liangcong Hu Bobin Mi Bobin Mi Adriana C. Panayi Hang Xue Hang Xue Yiqiang Hu Yiqiang Hu Guodong Liu Lang Chen Lang Chen Chenchen Yan Chenchen Yan Kangkang Zha Kangkang Zha Ze Lin Wu Zhou Wu Zhou Fei Gao Fei Gao Guohui Liu Guohui Liu SHIP1 Activator AQX-1125 Regulates Osteogenesis and Osteoclastogenesis Through PI3K/Akt and NF-κb Signaling Frontiers in Cell and Developmental Biology AQX-1125 SHIP1 bone loss osteoblast osteoclast |
| title | SHIP1 Activator AQX-1125 Regulates Osteogenesis and Osteoclastogenesis Through PI3K/Akt and NF-κb Signaling |
| title_full | SHIP1 Activator AQX-1125 Regulates Osteogenesis and Osteoclastogenesis Through PI3K/Akt and NF-κb Signaling |
| title_fullStr | SHIP1 Activator AQX-1125 Regulates Osteogenesis and Osteoclastogenesis Through PI3K/Akt and NF-κb Signaling |
| title_full_unstemmed | SHIP1 Activator AQX-1125 Regulates Osteogenesis and Osteoclastogenesis Through PI3K/Akt and NF-κb Signaling |
| title_short | SHIP1 Activator AQX-1125 Regulates Osteogenesis and Osteoclastogenesis Through PI3K/Akt and NF-κb Signaling |
| title_sort | ship1 activator aqx 1125 regulates osteogenesis and osteoclastogenesis through pi3k akt and nf κb signaling |
| topic | AQX-1125 SHIP1 bone loss osteoblast osteoclast |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.826023/full |
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