Therapy-Induced Senescence Drives Bone Loss

Cancer Res. 2020 Mar 1;80(5):1171-1182. doi: 10.1158/0008-5472.CAN-19-2348. Epub 2020 Jan 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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
  • Paclitaxel / adverse effects
  • Protein Serine-Threonine Kinases / metabolism
  • X-Ray Microtomography
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Antineoplastic Agents
  • Intracellular Signaling Peptides and Proteins
  • Doxorubicin
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Paclitaxel