@article{772c1ffed27f450f804ed2b8dcd86e1a,
title = "Therapy-induced senescence drives bone loss",
abstract = "Chemotherapy is important for cancer treatment, however, toxicities limit its use. While great strides have been made to ameliorate the acute toxicities induced by chemotherapy, longterm comorbidities including bone loss remain a significant problem. Chemotherapy-driven estrogen loss is postulated to drive bone loss, but significant data suggests the existence of an estrogen-independent mechanism of bone loss. Using clinically relevant mouse models, we showed that senescence and its senescence-associated secretory phenotype (SASP) contribute to chemotherapy-induced bone loss that can be rescued by depleting senescent cells. Chemotherapy-induced SASP could be limited by targeting the p38MAPK-MK2 pathway, which resulted in preservation of bone integrity in chemotherapy-treated mice. These results transform our understanding of chemotherapy-induced bone loss by identifying senescent cells as major drivers of bone loss and the p38MAPK-MK2 axis as a putative therapeutic target that can preserve bone and improve a cancer survivor's quality of life. Significance: Senescence drives chemotherapy-induced bone loss that is rescued by p38MAPK or MK2 inhibitors. These findings may lead to treatments for therapy-induced bone loss, significantly increasing quality of life for cancer survivors.",
author = "Zhangting Yao and Bhavna Murali and Qihao Ren and Xianmin Luo and Faget, {Douglas V.} and Tom Cole and Biancamaria Ricci and Dinesh Thotala and Joseph Monahan and {Van Deursen}, {Jan M.} and Darren Baker and Roberta Faccio and Schwarz, {Julie K.} and Stewart, {Sheila A.}",
note = "Funding Information: This work was supported by the Cancer Biology Pathway Molecular Oncology Training Grant NIH T32CA113275 (to B. Murali), NIH grantsR01CA130919(toS.A. Stewart), and R01 CA181745 (to J.K. Schwarz), and an American Cancer Society Research Scholar Award (to S.A. Stewart). The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014, is the awarding and administrating acquisition office, and this was supported in part by the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program, under award No. W81XWH-16-1-0728. This work was also supported by the Siteman Cancer Center Investment Program (NCI Cancer Center Support Grant P30CA091842, Fashion Footwear Association of New York, and the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund to S.A. Stewart), a Siteman Cancer Center grant to R. Faccio, NIH grants R01 AR053628 and R01 AR066551 to R. Faccio, and Shriners Hospital grant 85100 to R. Faccio, and J.K. Schwarz is supported by R01 CA181745. Finally, the Glenn Foundation for Medical Research (to J.M. van Deursen and D. Baker) and the NIH (AG057493 to J.M. van Deursen and AG053229 to D. Baker) also supported this work. We thank Deborah Veis and Matthew Silva for their valuable suggestions. We thank Crystal Idleburg and Samantha Coleman at the Musculoskeletal Histology core for their expert technical assistance with bone tissue sectioning and staining. In addition, we thank Daniel Leib, Yung Kim, and Michael Brodt in the Structure and Strength Musculoskeletal core for mCT imaging; Washington University Musculoskeletal Research Center (NIH P30 AR074992). Finally, we thank Lorry Blath and Judy Johnson for their constant support, enthusiasm, and critical assessment of our work and its impact on patients with breast cancer. Imaging and analysis of bone biopsy slides were performed using Zeiss Axio Scan Z.1 at the Washington University Center for Cellular Imaging, which is supported byWashington University School of Medicine, The Children's Discovery Institute of Washington University and St. Louis Children's Hospital (CDI-CORE-2015-505), and the National Institute for Neurological Disorders and Stroke (NS086741). The Centers are partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center. Finally, we thank Melissa Stauffer of Scientific Editing Solutions for editing the article. Funding Information: S.A. Stewart reports receiving a commercial research grant from Aclaris. J. Monahan is an executive vice president R&D (paid consultant) at Aclaris Therapeutics, Inc. D. Baker holds ownership interest (including patents) in Unity Biotechnology. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = mar,
day = "1",
doi = "10.1158/0008-5472.CAN-19-2348",
language = "English",
volume = "80",
pages = "1171--1182",
journal = "Cancer Research",
issn = "0008-5472",
number = "5",
}