Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 12, Issue 544, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aav9166
Keywords
-
Categories
Funding
- NIH [CA103866, AI047389, HD070394, T32DK007028-44]
- Department of Defense [W81XWH-07-0448]
- W.M. Keck Foundation
- LAM (lymphangioleiomyomatosis) Foundation
- Rolanette and Berdon Lawrence Bone Disease Program of Texas
- NIDDK [5T32DK060445-10]
- Shriners Hospitals for Children
- Jane Coffin Childs Foundation
- NIH/NIA [K99/R00 AG047255]
- NIH/NIAMS [K99 AR073903, R01 AR073017, P30 AR057235]
- NCI [2RO1CA129933]
- F30 NIH training grant
- BCM Center for Skeletal Medicine and Biology
- Merck Sharp Dohme
Ask authors/readers for more resources
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 A TRAID-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available