Therapy-Induced Senescence Drives Bone Loss
- 1 March 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (5), 1171-1182
- https://doi.org/10.1158/0008-5472.can-19-2348
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, long-term 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.Keywords
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Funding Information
- HHS | NIH | National Cancer Institute (CA130919)
- HHS | NIH | National Cancer Institute (CA181745)
- DOD | Congressionally Directed Medical Research Programs (W81XWH-16-1-0728)
- HHS | NIH | National Cancer Institute (P30CA091842)
- HHS | NIH | National Institute of General Medical Sciences (AR053628)
- HHS | NIH | National Institute on Aging (AG057493)
- HHS | NIH | National Institute on Aging (AG053229)
- Glenn Foundation for Medical Research
- Shriners Hospital (85100)
- Cancer Biology Pathway Molecular Training (T32CA113275)
- HHS (AR066551)
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