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ATRAID regulates the action of nitrogen-containing bisphosphonates on bone

Lauren E. Surface, Damon T. Burrow, Jinmei Li, Jiwoong Park, Sandeep Kumar, Cheng Lyu, Niki Song, Zhou Yu, Abbhirami Rajagopal, Yangjin Bae, Brendan H. Lee, Steven Mumm, Charles C. Gu, Jonathan C. Baker, Mahshid Mohseni, Melissa Sum, Margaret Huskey, Shenghui Duan, Vinieth N. Bijanki, Roberto Civitelli, Michael J. Gardner, Chris M. McAndrew, William M. Ricci, Christina A. Gurnett, Kathryn Diemer, Fei Wan, Christina L. Costantino, Kristen M. Shannon, Noopur Raje, Thomas B. Dodson, Daniel A. Haber, Jan E. Carette, Malini Varadarajan, Thijn R. Brummelkamp, Kivanc Birsoy, David M. Sabatini, Gabe Haller, View ORCID ProfileTimothy R. Peterson
doi: https://doi.org/10.1101/338350
Lauren E. Surface
1Department of Molecular and Cellular Biology, Department of Chemistry and Chemical Biology, Faculty of Arts and Sciences Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA
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Damon T. Burrow
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Jinmei Li
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Jiwoong Park
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Sandeep Kumar
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Cheng Lyu
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Niki Song
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Zhou Yu
1Department of Molecular and Cellular Biology, Department of Chemistry and Chemical Biology, Faculty of Arts and Sciences Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA
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Abbhirami Rajagopal
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
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Yangjin Bae
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
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Brendan H. Lee
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
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Steven Mumm
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
4Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63110, USA
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Charles C. Gu
5Division of Biostatistics, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8067, St. Louis, MO 63110, USA
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Jonathan C. Baker
6Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd. Louis, MO 63110, USA
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Mahshid Mohseni
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Melissa Sum
7Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, 530 1st Ave., Schwartz 5E. New York, NY 10016, USA
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Margaret Huskey
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Shenghui Duan
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Vinieth N. Bijanki
4Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63110, USA
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Roberto Civitelli
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Michael J. Gardner
8Stanford University, Department of Orthopedic Surgery, 450 Broadway Street, Redwood City, CA 94063, USA
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Chris M. McAndrew
9Department of Orthopedic Surgery, Washington University School of Medicine, 4938 Parkview Place, St. Louis, MO 63110, USA
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William M. Ricci
10Hospital for Special Surgery Main Campus - Belaire Building, 525 East 71st Street 2nd Floor, New York, NY 10021, USA
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Christina A. Gurnett
9Department of Orthopedic Surgery, Washington University School of Medicine, 4938 Parkview Place, St. Louis, MO 63110, USA
11Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S. Euclid Ave., St. Louis, MO 63110, USA
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Kathryn Diemer
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
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Fei Wan
12Department of Surgery, Washington University School of Medicine, Campus Box 8109, 4590 Children’s Place, Suite 9600, St. Louis, MO 63110, USA
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Christina L. Costantino
13Massachusetts General Hospital Cancer Center and Department of Surgery, Harvard Medical School, Boston, MA 02114, USA
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Kristen M. Shannon
14Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
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Noopur Raje
14Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
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Thomas B. Dodson
15Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital and Harvard School of Dental Medicine, Boston, MA 02114, USA
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Daniel A. Haber
14Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
16Howard Hughes Medical Institute (HHMI), Chevy Chase, MD 20815, USA
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Jan E. Carette
17Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
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Malini Varadarajan
18Oncology Disease Area, Novartis institutes for biomedical research, Cambridge, CA 02140, USA
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Thijn R. Brummelkamp
19Oncode Institute, Division of Biochemistry, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, Netherlands
20CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
21Cancer Genomics Center, Plesmanlaan 121, 1066CX, Amsterdam, Netherlands
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Kivanc Birsoy
22The Rockefeller University, 1230 York Ave, New York 10065, USA
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David M. Sabatini
16Howard Hughes Medical Institute (HHMI), Chevy Chase, MD 20815, USA
23Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02139, USA
24Department of Biology, Massachusetts Institute of Technology (MIT), 77 Massachusetts Avenue, Cambridge, MA 02139, USA
25David H. Koch Center for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
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Gabe Haller
11Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S. Euclid Ave., St. Louis, MO 63110, USA
26Department of Neurosurgery, Washington University School of Medicine, Campus Box 8057, 660 S. Euclid Ave., St. Louis, MO 63110, USA
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Timothy R. Peterson
2Division of Bone & Mineral Diseases, Department of Medicine, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave., St. Louis, MO 63110, USA
27Department of Genetics, Washington University School of Medicine, 4515 McKinley Ave. Campus Box 8232, St. Louis, MO 63110, USA
28Institute for Public Health, Washington University School of Medicine, 600 S. Taylor Suite 2400, Campus Box 8217, St. Louis, MO 63110, USA
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  • ORCID record for Timothy R. Peterson
  • For correspondence: timrpeterson@wustl.edu
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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 (AFFs) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), 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. Lastly, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare non-synonymous coding variants in patients with ONJ or 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.

One Sentence Summary ATRAID is essential for responses to the commonly prescribed osteoporosis drugs nitrogen-containing bisphosphonates.

Overline BONE

Competing Interest Statement

ATRAID, SNTG1, EPHB1, and PLCL1, the genes identified here, are part of a Whitehead–Harvard patent on which T.R.P., T.R.B., and D.M.S. are inventors (US8748097B1).

Footnotes

  • The discussion section was expanded. Many grammatical changes throughout. Figures were cleaned up.

  • https://github.com/tim-peterson/ATRAID

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 10, 2020.
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ATRAID regulates the action of nitrogen-containing bisphosphonates on bone
Lauren E. Surface, Damon T. Burrow, Jinmei Li, Jiwoong Park, Sandeep Kumar, Cheng Lyu, Niki Song, Zhou Yu, Abbhirami Rajagopal, Yangjin Bae, Brendan H. Lee, Steven Mumm, Charles C. Gu, Jonathan C. Baker, Mahshid Mohseni, Melissa Sum, Margaret Huskey, Shenghui Duan, Vinieth N. Bijanki, Roberto Civitelli, Michael J. Gardner, Chris M. McAndrew, William M. Ricci, Christina A. Gurnett, Kathryn Diemer, Fei Wan, Christina L. Costantino, Kristen M. Shannon, Noopur Raje, Thomas B. Dodson, Daniel A. Haber, Jan E. Carette, Malini Varadarajan, Thijn R. Brummelkamp, Kivanc Birsoy, David M. Sabatini, Gabe Haller, Timothy R. Peterson
bioRxiv 338350; doi: https://doi.org/10.1101/338350
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ATRAID regulates the action of nitrogen-containing bisphosphonates on bone
Lauren E. Surface, Damon T. Burrow, Jinmei Li, Jiwoong Park, Sandeep Kumar, Cheng Lyu, Niki Song, Zhou Yu, Abbhirami Rajagopal, Yangjin Bae, Brendan H. Lee, Steven Mumm, Charles C. Gu, Jonathan C. Baker, Mahshid Mohseni, Melissa Sum, Margaret Huskey, Shenghui Duan, Vinieth N. Bijanki, Roberto Civitelli, Michael J. Gardner, Chris M. McAndrew, William M. Ricci, Christina A. Gurnett, Kathryn Diemer, Fei Wan, Christina L. Costantino, Kristen M. Shannon, Noopur Raje, Thomas B. Dodson, Daniel A. Haber, Jan E. Carette, Malini Varadarajan, Thijn R. Brummelkamp, Kivanc Birsoy, David M. Sabatini, Gabe Haller, Timothy R. Peterson
bioRxiv 338350; doi: https://doi.org/10.1101/338350

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