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ATRAID regulates the action of nitrogen-containing bisphosphonates on bone.

Abstract：

: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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Surface LE,Burrow DT,Li J,Park J,Kumar S,Lyu C,Song N,Yu Z,Rajagopal A,Bae Y,Lee BH,Mumm S,Gu CC,Baker JC,Mohseni M,Sum M,Huskey M,Duan S,Bijanki VN,Civitelli R,Gardner MJ,McAndrew CM,Ricci WM,Gurnett CA,D

doi

10.1126/scitranslmed.aav9166

subject

Has Abstract

pub_date

2020-05-20 00:00:00

issue

544

eissn

1946-6234

issn

1946-6242

pii

12/544/eaav9166

journal_volume

12

pub_type

杂志文章

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