Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase
Objective: Donepezil, an inhibitor of acetylcholinesterase (AChE) targeting the brain, is a common medication for Alzheimer's disease. Interestingly, a recent clinical study found that administration of this agent is associated with lower risk of hip fracture independently of falling, suggestin...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2015-09-01
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| Series: | Heliyon |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844015302620 |
| _version_ | 1828832728711168000 |
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| author | Tsuyoshi Sato Yuichiro Enoki Yasushi Sakamoto Kazuhiro Yokota Masahiko Okubo Masahito Matsumoto Naoki Hayashi Michihiko Usui Shoichiro Kokabu Toshihide Mimura Yoshihiko Nakazato Nobuo Araki Toru Fukuda Yasushi Okazaki Tatsuo Suda Shu Takeda Tetsuya Yoda |
| author_facet | Tsuyoshi Sato Yuichiro Enoki Yasushi Sakamoto Kazuhiro Yokota Masahiko Okubo Masahito Matsumoto Naoki Hayashi Michihiko Usui Shoichiro Kokabu Toshihide Mimura Yoshihiko Nakazato Nobuo Araki Toru Fukuda Yasushi Okazaki Tatsuo Suda Shu Takeda Tetsuya Yoda |
| author_sort | Tsuyoshi Sato |
| collection | DOAJ |
| description | Objective: Donepezil, an inhibitor of acetylcholinesterase (AChE) targeting the brain, is a common medication for Alzheimer's disease. Interestingly, a recent clinical study found that administration of this agent is associated with lower risk of hip fracture independently of falling, suggesting its direct effect on bone tissues as well. AChE has been reported to be involved in osteoblast function, but the role of AChE on osteoclastogenesis still remains unclear. We analyzed the effect of AChE and donepezil on osteoclastogenesis in vivo and in vitro.
Methods: Cell-based assays were conducted using osteoclasts generated in cultures of murine bone marrow macrophages (BMMs) with receptor activator of nuclear factor-kappa B ligand (RANKL). The effect of donepezil was also determined in vivo using a mouse model of RANKL-induced bone loss.
Results: Recombinant AChE in BMMs cultured with RANKL further promoted RANKL-induced tartrate-resistant acid phosphatase (TRAP)-positive osteoclast differentiation. RANKL also upregulated AChE expression in BMMs. RNA interference-mediated knockdown of AChE significantly inhibited RANKL-induced osteoclast differentiation and suppressed gene expression specific for osteoclasts. AChE upregulated expression of RANK, the receptor of RANKL, in BMMs. Donepezil decreased cathepsin K expression in BMMs and the resorptive function of osteoclasts on dentine slices. Donepezil decreased RANK expression in BMMs, resulting in the inhibition of osteoclast differentiation with downregulation of c-Fos and upregulation of Id2. Moreover, administration of donepezil prevented RANKL-induced bone loss in vivo, which was associated with the inhibition of bone resorption by osteoclasts.
Conclusions: AChE promotes osteoclast differentiation in vitro. Donepezil inhibits osteoclast function in vitro and prevents bone loss by suppressing bone resorption in vivo, suggesting the possibility that donepezil reduces fracture risk in patients with Alzheimer's disease. |
| first_indexed | 2024-12-12T17:00:12Z |
| format | Article |
| id | doaj.art-507f8d320d184a8a83d7cfd3bceb421b |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-12-12T17:00:12Z |
| publishDate | 2015-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-507f8d320d184a8a83d7cfd3bceb421b2022-12-22T00:18:08ZengElsevierHeliyon2405-84402015-09-011110.1016/j.heliyon.2015.e00013Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesteraseTsuyoshi Sato0Yuichiro Enoki1Yasushi Sakamoto2Kazuhiro Yokota3Masahiko Okubo4Masahito Matsumoto5Naoki Hayashi6Michihiko Usui7Shoichiro Kokabu8Toshihide Mimura9Yoshihiko Nakazato10Nobuo Araki11Toru Fukuda12Yasushi Okazaki13Tatsuo Suda14Shu Takeda15Tetsuya Yoda16Department of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, JapanDepartment of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, JapanDepartment of Biomedical Research Center, Division of Analytical Science, Saitama Medical University, Saitama, JapanDepartment of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, JapanDepartment of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, JapanDivision of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, JapanDepartment of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, JapanDepartment of Periodontology, Kyushu Dental University, Fukuoka, JapanDivision of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Fukuoka, JapanDepartment of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, JapanDepartment of Neurology, Saitama Medical University, Saitama, JapanDepartment of Neurology, Saitama Medical University, Saitama, JapanDepartment of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, JapanDivision of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, JapanDivision of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, JapanDepartment of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, JapanObjective: Donepezil, an inhibitor of acetylcholinesterase (AChE) targeting the brain, is a common medication for Alzheimer's disease. Interestingly, a recent clinical study found that administration of this agent is associated with lower risk of hip fracture independently of falling, suggesting its direct effect on bone tissues as well. AChE has been reported to be involved in osteoblast function, but the role of AChE on osteoclastogenesis still remains unclear. We analyzed the effect of AChE and donepezil on osteoclastogenesis in vivo and in vitro. Methods: Cell-based assays were conducted using osteoclasts generated in cultures of murine bone marrow macrophages (BMMs) with receptor activator of nuclear factor-kappa B ligand (RANKL). The effect of donepezil was also determined in vivo using a mouse model of RANKL-induced bone loss. Results: Recombinant AChE in BMMs cultured with RANKL further promoted RANKL-induced tartrate-resistant acid phosphatase (TRAP)-positive osteoclast differentiation. RANKL also upregulated AChE expression in BMMs. RNA interference-mediated knockdown of AChE significantly inhibited RANKL-induced osteoclast differentiation and suppressed gene expression specific for osteoclasts. AChE upregulated expression of RANK, the receptor of RANKL, in BMMs. Donepezil decreased cathepsin K expression in BMMs and the resorptive function of osteoclasts on dentine slices. Donepezil decreased RANK expression in BMMs, resulting in the inhibition of osteoclast differentiation with downregulation of c-Fos and upregulation of Id2. Moreover, administration of donepezil prevented RANKL-induced bone loss in vivo, which was associated with the inhibition of bone resorption by osteoclasts. Conclusions: AChE promotes osteoclast differentiation in vitro. Donepezil inhibits osteoclast function in vitro and prevents bone loss by suppressing bone resorption in vivo, suggesting the possibility that donepezil reduces fracture risk in patients with Alzheimer's disease.http://www.sciencedirect.com/science/article/pii/S2405844015302620AcetylcholinesteraseOsteoclastDonepezilAlzheimer's diseaseDifferentiation |
| spellingShingle | Tsuyoshi Sato Yuichiro Enoki Yasushi Sakamoto Kazuhiro Yokota Masahiko Okubo Masahito Matsumoto Naoki Hayashi Michihiko Usui Shoichiro Kokabu Toshihide Mimura Yoshihiko Nakazato Nobuo Araki Toru Fukuda Yasushi Okazaki Tatsuo Suda Shu Takeda Tetsuya Yoda Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase Heliyon Acetylcholinesterase Osteoclast Donepezil Alzheimer's disease Differentiation |
| title | Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase |
| title_full | Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase |
| title_fullStr | Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase |
| title_full_unstemmed | Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase |
| title_short | Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase |
| title_sort | donepezil prevents rank induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase |
| topic | Acetylcholinesterase Osteoclast Donepezil Alzheimer's disease Differentiation |
| url | http://www.sciencedirect.com/science/article/pii/S2405844015302620 |
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