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Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL.

ABSTRACT: Radiation therapy is an integral part of treatment for cancer patients; however, major side effects of this modality include aberrant bone remodeling and bone loss. Ionizing radiation (IR) is a major external factor that contributes to a significant increase in oxidative stress such as reactive oxygen species (ROS), has been implicated in osteoporotic phenotypes, and has been implicated in osteoporotic phenotypes, bone loss, and fracture risk. One of the major cellular defenses against heightened oxidative stress is mediated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master transcription factor that regulates induction of antioxidant gene expression and phase II antioxidant enzymes. Our objective was to test the hypothesis that loss of functional Nrf2 increases radiation-induced bone loss. We irradiated (single dose, 20Gy) the hindlegs of age- and sex-matched Nrf2(+/+) and Nrf2(-/-) mice. After 1 month, microCT analysis and histology revealed a drastic overall decrease in the bone volume after irradiation of mice lacking Nrf2. Although radiation exposure led to bone loss in mice with intact Nrf2, it was dramatically enhanced by loss of Nrf2. Furthermore, in the absence of Nrf2, a decrease in osteoblast mineralization was noted in calvarial osteoblasts compared with wild-type controls, and treatment with a common antioxidant, N-acetyl-l-cysteine (NAC), was able to rescue the mineralization. As expected, we observed a higher number of osteoclasts in Nrf2(-/-) mice compared to Nrf2(+/+) mice, and after irradiation, the trend remained the same. RT-PCR analysis of calvarial osteoblasts revealed that in the absence of Nrf2, the expression of RANKL was increased after irradiation. Interestingly, RANKL expression was suppressed when the calvarial osteoblasts were treated with NAC before IR exposure. Taken together, our data suggest that loss of Nrf2 leads to heightened oxidative stress and increased susceptibility to radiation-induced bone loss.

SUBMITTER: Rana T

PROVIDER: S-EPMC3762920 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL.

Rana Tapasi T Schultz Michelle A MA Freeman Michael L ML Biswas Swati S

Free radical biology & medicine 20121022 12

Radiation therapy is an integral part of treatment for cancer patients; however, major side effects of this modality include aberrant bone remodeling and bone loss. Ionizing radiation (IR) is a major external factor that contributes to a significant increase in oxidative stress such as reactive oxygen species (ROS), has been implicated in osteoporotic phenotypes, and has been implicated in osteoporotic phenotypes, bone loss, and fracture risk. One of the major cellular defenses against heightene ...[more]

PMID: 23085426

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Project description:Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone. Presently, no effective countermeasure exists, and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity. The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy. Our studies revealed that P7C3 repressed ionizing radiation (IR)-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition in vitro. We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened, osteoporotic bone. However, the administration of P7C3 significantly inhibited osteoclastic activity, lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area, architecture, and mechanical strength. Our findings revealed significant enhancement of cellular macromolecule metabolic processes, myeloid cell differentiation, and the proteins LRP-4, TAGLN, ILK, and Tollip, with downregulation of GDF-3, SH2B1, and CD200. These proteins are key in favoring osteoblast over adipogenic progenitor differentiation, cell matrix interactions, and shape and motility, facilitating inflammatory resolution, and suppressing osteoclastogenesis, potentially via Wnt/β-catenin signaling. A concern was whether P7C3 afforded similar protection to cancer cells. Preliminarily, and remarkably, at the same protective P7C3 dose, a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro. Together, these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy, leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications. Our data uncover a new approach for the prevention of radiation-induced bone damage, and further work is needed to investigate its ability to selectively drive cancer cell death.

Dataset Information

Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL.

Publications

Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL.

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