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FASEB J. 2018 Jan;32(1):52-62. doi: 10.1096/fj.201700375R. Epub 2017 Aug 31.

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

Author information

1
Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
2
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.
3
Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
4
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
5
Division of Endocrinology and Diabetes Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
6
Center for Bone Health, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
7
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
8
Department of Physical Medicine and Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
9
Translational Musculoskeletal Research Center (TMRC), Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.
10
Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; qinling@mail.med.upenn.edu.

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.

KEYWORDS:

DNA repair; apoptosis; bone; irradiation; osteoblast

PMID:
28860152
PMCID:
PMC5731129
DOI:
10.1096/fj.201700375R
[Indexed for MEDLINE]
Free PMC Article

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