Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis.

Abstract

Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up-regulation of Ku70 and DNA-dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end-joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone-lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation-induced osteoporosis.-Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.-J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis.

• Authors: Abhishek Chandra, Luqiang Wang, Tiffany Young, Leilei Zhong, Wei-Ju Tseng, Michael A Levine, Keith Cengel, X Sherry Liu, Yejia Zhang, Robert J Pignolo, Ling Qin
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 32 Issue 1 Pg. 52-62 (01 2018) ISSN: 1530-6860 [Electronic] United States
• PMID: 28860152 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © FASEB.

Chemical References

• Proteasome Inhibitors
• Radiation-Protective Agents
• Bortezomib

Topics

• 3T3 Cells
• Animals
• Apoptosis (drug effects, radiation effects)
• Bone Remodeling (drug effects, radiation effects)
• Bortezomib (pharmacology)
• Cell Line
• Cell Survival (drug effects)
• DNA Repair (drug effects)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Osteoblasts (drug effects, pathology, radiation effects)
• Osteoporosis (drug therapy, metabolism, pathology)
• Proteasome Inhibitors (pharmacology)
• Radiation Injuries (drug therapy, metabolism, pathology)
• Radiation-Protective Agents (pharmacology)
• X-Ray Microtomography