Therapy-Induced Senescence Drives Bone Loss

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2020-03, Vol.80 (5), p.1171-1182
Main Authors: Yao, Zhangting, Murali, Bhavna, Ren, Qihao, Luo, Xianmin, Faget, Douglas V, Cole, Tom, Ricci, Biancamaria, Thotala, Dinesh, Monahan, Joseph, van Deursen, Jan M, Baker, Darren, Faccio, Roberta, Schwarz, Julie K, Stewart, Sheila A
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - adverse effects
Cellular Senescence - drug effects
Disease Models, Animal
Doxorubicin - adverse effects
Femur - cytology
Femur - diagnostic imaging
Femur - pathology
Humans
Injections, Intraperitoneal
Intracellular Signaling Peptides and Proteins - metabolism
MAP Kinase Signaling System - drug effects
Mice
Mice, Transgenic
Neoplasms - drug therapy
Osteoporosis - chemically induced
Osteoporosis - diagnosis
Osteoporosis - pathology
p38 Mitogen-Activated Protein Kinases - metabolism
Paclitaxel - adverse effects
Protein Serine-Threonine Kinases - metabolism
X-Ray Microtomography
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-19-2348