Therapy-Induced Senescence Drives Bone Loss

• 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
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-19-2348

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.