RT Journal Article
SR Electronic
T1 ATRAID, a genetic factor that regulates the clinical action of nitrogen-containing bisphosphonates on bone
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 338350
DO 10.1101/338350
A1 Lauren E. Surface
A1 JiWoong Park
A1 Sandeep Kumar
A1 Damon T. Burrow
A1 Cheng Lyu
A1 Jinmei Li
A1 Niki Song
A1 Zhou Yu
A1 Abbhirami Rajagopal
A1 Yangjin Bae
A1 Brendan H. Lee
A1 Steven Mumm
A1 Gabe Haller
A1 Charles C. Gu
A1 Jonathan C. Baker
A1 Mahshid Mohseni
A1 Melissa Sum
A1 Margaret Huskey
A1 Shenghui Duan
A1 Vinieth N. Bijanki
A1 Roberto Civitelli
A1 Michael J. Gardner
A1 Chris M. McAndrew
A1 William M. Ricci
A1 Christina A. Gurnett
A1 Kathryn Diemer
A1 Michael P. Whyte
A1 Jan E. Carette
A1 Malini Varadarajan
A1 Thijn R. Brummelkamp
A1 Kivanc Birsoy
A1 David M. Sabatini
A1 Erin K. O’Shea
A1 Timothy R. Peterson
YR 2018
UL http://biorxiv.org/content/early/2018/06/04/338350.abstract
AB Nitrogen-containing bisphosphonates (N-BPs), such as alendronate (Fosamax®), are the mostly widely prescribed medications for diseases involving bone1-3, with nearly 200 million prescriptions written annually. In the last few years, widespread use of N-BPs has been challenged due to the risk of rare but significant side effects such as atypical femoral fractures and osteonecrosis of the jaw4-7. N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), resulting in defects in protein prenylation8-10. Yet it remains poorly understood what other cellular targets N-BPs might have. Herein, we perform genome-wide studies in cells and patients to identify the gene, ATRAID, that functions with FDPS in a novel pathway we name the TBONE (Target of Bisphosphonates) pathway. 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 a model of postmenopausal osteoporosis. 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.One Sentence Summary The identification of the gene, ATRAID, essential for responses to the commonly prescribed osteoporosis (i.e., bone loss) drugs, nitrogen-containing bisphosphonates.