TY - JOUR
T1 - ATRAID regulates the action of nitrogen-containing bisphosphonates on bone
AU - Surface, Lauren E.
AU - Burrow, Damon T.
AU - Li, Jinmei
AU - Park, Jiwoong
AU - Kumar, Sandeep
AU - Lyu, Cheng
AU - Song, Niki
AU - Yu, Zhou
AU - Rajagopal, Abbhirami
AU - Bae, Yangjin
AU - Lee, Brendan H.
AU - Mumm, Steven
AU - Gu, Charles C.
AU - Baker, Jonathan C.
AU - Mohseni, Mahshid
AU - Sum, Melissa
AU - Huskey, Margaret
AU - Duan, Shenghui
AU - Bijanki, Vinieth N.
AU - Civitelli, Roberto
AU - Gardner, Michael J.
AU - McAndrew, Chris M.
AU - Ricci, William M.
AU - Gurnett, Christina A.
AU - Diemer, Kathryn
AU - Wan, Fei
AU - Costantino, Christina L.
AU - Shannon, Kristen M.
AU - Raje, Noopur
AU - Dodson, Thomas B.
AU - Haber, Daniel A.
AU - Carette, Jan E.
AU - Varadarajan, Malini
AU - Brummelkamp, Thijn R.
AU - Birsoy, Kivanc
AU - Sabatini, David M.
AU - Haller, Gabe
AU - Peterson, Timothy R.
N1 - Funding Information:
This work was supported by grants from the NIH (CA103866 and AI047389 to D.M.S. and HD070394 to B.H.L.) and Department of Defense (W81XWH-07-0448 to D.M.S.); awards from the W.M. Keck Foundation and the LAM (lymphangioleiomyomatosis) Foundation to D.M.S.; Rolanette and Berdon Lawrence Bone Disease Program of Texas and BCM Center for Skeletal Medicine and Biology and NIDDK training grant 5T32DK060445-10 to A.R.; Shriners Hospitals for Children and Merck Sharp & Dohme to S.M.; Fellowship from the Jane Coffin Childs Foundation and NIH/NIA K99/R00 AG047255, NIH/NIAMS R01 AR073017, and NIH/NIAMS P30 AR057235 to T.R.P; NIH T32DK007028-44 and NIH/NIAMS K99 AR073903 to L.E.S. D.M.S. is an investigator of the Howard Hughes Medical Institute. NCI 2RO1CA129933 to D.A.H., who is also an investigator of the Howard Hughes Medical Institute and a F30 NIH training grant to C.L.C.
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved.
PY - 2020/5/20
Y1 - 2020/5/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084965181&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aav9166
DO - 10.1126/scitranslmed.aav9166
M3 - Article
C2 - 32434850
AN - SCOPUS:85084965181
SN - 1946-6234
VL - 12
JO - Science translational medicine
JF - Science translational medicine
IS - 544
M1 - eaav9166
ER -