We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Radiation-induced bone loss in mice is ameliorated by inhibition of HIF-2α in skeletal progenitor cells.
- Authors
Guo, Wendi; Hoque, Jiaul; Garcia Garcia, Carolina J.; Spiller, Kassandra V.; Leinroth, Abigail P.; Puviindran, Vijitha; Potnis, Cahil K.; Gunn, Kiana A.; Newman, Hunter; Ishikawa, Koji; Fujimoto, Tara N.; Neill, Denae W.; Delahoussaye, Abagail M.; Williams, Nerissa T.; Kirsch, David G.; Hilton, Matthew J.; Varghese, Shyni; Taniguchi, Cullen M.; Wu, Colleen
- Abstract
Radiotherapy remains a common treatment modality for cancer despite skeletal complications. However, there are currently no effective treatments for radiation-induced bone loss, and the consequences of radiotherapy on skeletal progenitor cell (SPC) survival and function remain unclear. After radiation, leptin receptor–expressing cells, which include a population of SPCs, become localized to hypoxic regions of the bone and stabilize the transcription factor hypoxia-inducible factor-2α (HIF-2α), thus suggesting a role for HIF-2α in the skeletal response to radiation. Here, we conditionally knocked out HIF-2α in leptin receptor–expressing cells and their descendants in mice. Radiation therapy in littermate control mice reduced bone mass; however, HIF-2α conditional knockout mice maintained bone mass comparable to nonirradiated control animals. HIF-2α negatively regulated the number of SPCs, bone formation, and bone mineralization. To test whether blocking HIF-2α pharmacologically could reduce bone loss during radiation, we administered a selective HIF-2α inhibitor called PT2399 (a structural analog of which was recently FDA-approved) to wild-type mice before radiation exposure. Pharmacological inhibition of HIF-2α was sufficient to prevent radiation-induced bone loss in a single-limb irradiation mouse model. Given that ~90% of patients who receive a HIF-2α inhibitor develop anemia because of off-target effects, we developed a bone-targeting nanocarrier formulation to deliver the HIF-2α inhibitor to mouse bone, to increase on-target efficacy and reduce off-target toxicities. Nanocarrier-loaded PT2399 prevented radiation-induced bone loss in mice while reducing drug accumulation in the kidney. Targeted inhibition of HIF-2α may represent a therapeutic approach for protecting bone during radiation therapy. Editor's summary: Radiotherapy frequently leads to bone loss. Here, Guo and colleagues explored the role of hypoxia signaling through HIF-2α in skeletal progenitor cells as a negative regulator of bone mass after radiotherapy in mice. Selective knockout of HIF-2α in leptin receptor-expressing skeletal progenitor cells rescued mice from decreased bone mass after total body irradiation. Pharmacologic inhibition of HIF-2α improved bone integrity; however, systemic treatment caused off-target effects. Therefore, a bone-targeting nanocarrier was developed to deliver localized HIF-2α inhibition, which alleviated radiation-induced bone loss without systemic off-target effects. This represents a promising targeted strategy that awaits further clinical validation. —Molly Ogle
- Subjects
UNITED States. Food &; Drug Administration; LEPTIN; PROGENITOR cells; TOTAL body irradiation; MICE; HYPOXIA-inducible factors; RADIATION exposure
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 724, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abo5217