ATRAID regulates the action of nitrogen-containing bisphosphonates on bone
Copyright © 2020 The Authors, some rights reserved. Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
American Association for the Advancement of Science (AAAS)
2022
|
| Online Access: | https://hdl.handle.net/1721.1/133570.2 |
| _version_ | 1811083580117352448 |
|---|---|
| author | Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Sabatini, David |
| author_sort | Sabatini, David |
| collection | MIT |
| description | Copyright © 2020 The Authors, some rights reserved. Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase, resulting in defects in protein prenylation. Yet, it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP–mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Last, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare nonsynonymous coding variants in patients with ONJ or an AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people. |
| first_indexed | 2024-09-23T12:35:20Z |
| format | Article |
| id | mit-1721.1/133570.2 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:35:20Z |
| publishDate | 2022 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/133570.22022-09-26T18:04:51Z ATRAID regulates the action of nitrogen-containing bisphosphonates on bone Sabatini, David Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Whitehead Institute for Biomedical Research Copyright © 2020 The Authors, some rights reserved. Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase, resulting in defects in protein prenylation. Yet, it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP–mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Last, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare nonsynonymous coding variants in patients with ONJ or an AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people. 2022-09-26T18:04:50Z 2021-10-27T19:53:34Z 2022-09-26T18:04:50Z 2020 2021-07-23T18:49:22Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133570.2 en 10.1126/SCITRANSLMED.AAV9166 Science Translational Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/octet-stream American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Sabatini, David ATRAID regulates the action of nitrogen-containing bisphosphonates on bone |
| title | ATRAID regulates the action of nitrogen-containing bisphosphonates on bone |
| title_full | ATRAID regulates the action of nitrogen-containing bisphosphonates on bone |
| title_fullStr | ATRAID regulates the action of nitrogen-containing bisphosphonates on bone |
| title_full_unstemmed | ATRAID regulates the action of nitrogen-containing bisphosphonates on bone |
| title_short | ATRAID regulates the action of nitrogen-containing bisphosphonates on bone |
| title_sort | atraid regulates the action of nitrogen containing bisphosphonates on bone |
| url | https://hdl.handle.net/1721.1/133570.2 |
| work_keys_str_mv | AT sabatinidavid atraidregulatestheactionofnitrogencontainingbisphosphonatesonbone |