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

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

Research output: Contribution to journalArticle

11 Scopus citations

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 gH2AX 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.

Original languageEnglish (US)
Pages (from-to)52-62
Number of pages11
JournalFASEB Journal
Volume32
Issue number1
DOIs
StatePublished - Jan 2018

Keywords

  • Apoptosis
  • Bone
  • DNA repair
  • Irradiation
  • Osteoblast

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W. J., Levine, M. A., Cengel, K., Sherry Liu, X., Zhang, Y., Pignolo, R. J., & Qin, L. (2018). Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis. FASEB Journal, 32(1), 52-62. https://doi.org/10.1096/fj.201700375R