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Title: Ionizing radiation stimulates expression of pro-osteoclastogenic genes in marrow and skeletal tissue

Abstract

Exposure to ionizing radiation can cause rapid mineral loss and increase bone-resorbing osteoclasts within metabolically active, cancellous bone tissue leading to structural deficits. To better understand mechanisms involved in rapid, radiation-induced bone loss, we determined the influence of total body irradiation on expression of select cytokines known both to stimulate osteoclastogenesis and contribute to inflammatory bone disease. Adult (16 week), male C57BL/6J mice were exposed to either 2 Gy gamma rays ( 137Cs, 0.8 Gy/min) or heavy ions ( 56Fe, 600MeV, 0.50–1.1 Gy/min); this dose corresponds to either a single fraction of radiotherapy (typical total dose is ≥10 Gy) or accumulates over long-duration interplanetary missions. Serum, marrow, and mineralized tissue were harvested 4 h—7 days later. Gamma irradiation caused a prompt (2.6-fold within 4 h) and persistent (peaking at 4.1-fold within 1 day) rise in the expression of the obligate osteoclastogenic cytokine, receptor activator of nuclear factor kappa-B ligand ( Rankl), within marrow cells over controls. Similarly, Rankl expression peaked in marrow cells within 3 days of iron exposure (9.2-fold). Changes in Rankl expression induced by gamma irradiation preceded and overlapped with a rise in expression of other pro-osteoclastic cytokines in marrow (eg, monocyte chemotactic protein-1 increased by 11.9-fold, andmore » tumor necrosis factor-alpha increased by 1.7-fold over controls). The ratio, Rankl/ Opg, in marrow increased by 1.8-fold, a net pro-resorption balance. In the marrow, expression of the antioxidant transcription factor, Nfe2l2, strongly correlated with expression levels of Nfatc1, Csf1, Tnf, and Rankl. Radiation exposure increased a serum marker of bone resorption (tartrate-resistant acid phosphatase) and led to cancellous bone loss (16% decrement after 1 week). Finally, we conclude that total body irradiation (gamma or heavy-ion) caused temporal elevations in the concentrations of specific genes expressed within marrow and mineralized tissue related to bone resorption, including select cytokines that lead to osteoclastogenesis and elevated resorption; this is likely to account for rapid and progressive deterioration of cancellous microarchitecture following exposure to ionizing radiation.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. NASA Ames Research Center, Moffett Field, CA (United States). Bone and Signaling Lab., Space Biosciences Division
Publication Date:
Research Org.:
NASA Ames Research Center (ARC), Moffett Field, Mountain View, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1342731
Grant/Contract Number:  
SC0001507
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Interferon & Cytokine Research
Additional Journal Information:
Journal Volume: 35; Journal Issue: 6; Journal ID: ISSN 1079-9907
Publisher:
Mary Ann Liebert, Inc.
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.

Citation Formats

Alwood, Joshua S., Shahnazari, Mohammad, Chicana, Betsabel, Schreurs, A. S., Kumar, Akhilesh, Bartolini, Alana, Shirazi-Fard, Yasaman, and Globus, Ruth K. Ionizing radiation stimulates expression of pro-osteoclastogenic genes in marrow and skeletal tissue. United States: N. p., 2015. Web. doi:10.1089/jir.2014.0152.
Alwood, Joshua S., Shahnazari, Mohammad, Chicana, Betsabel, Schreurs, A. S., Kumar, Akhilesh, Bartolini, Alana, Shirazi-Fard, Yasaman, & Globus, Ruth K. Ionizing radiation stimulates expression of pro-osteoclastogenic genes in marrow and skeletal tissue. United States. doi:10.1089/jir.2014.0152.
Alwood, Joshua S., Shahnazari, Mohammad, Chicana, Betsabel, Schreurs, A. S., Kumar, Akhilesh, Bartolini, Alana, Shirazi-Fard, Yasaman, and Globus, Ruth K. Tue . "Ionizing radiation stimulates expression of pro-osteoclastogenic genes in marrow and skeletal tissue". United States. doi:10.1089/jir.2014.0152. https://www.osti.gov/servlets/purl/1342731.
@article{osti_1342731,
title = {Ionizing radiation stimulates expression of pro-osteoclastogenic genes in marrow and skeletal tissue},
author = {Alwood, Joshua S. and Shahnazari, Mohammad and Chicana, Betsabel and Schreurs, A. S. and Kumar, Akhilesh and Bartolini, Alana and Shirazi-Fard, Yasaman and Globus, Ruth K.},
abstractNote = {Exposure to ionizing radiation can cause rapid mineral loss and increase bone-resorbing osteoclasts within metabolically active, cancellous bone tissue leading to structural deficits. To better understand mechanisms involved in rapid, radiation-induced bone loss, we determined the influence of total body irradiation on expression of select cytokines known both to stimulate osteoclastogenesis and contribute to inflammatory bone disease. Adult (16 week), male C57BL/6J mice were exposed to either 2 Gy gamma rays (137Cs, 0.8 Gy/min) or heavy ions (56Fe, 600MeV, 0.50–1.1 Gy/min); this dose corresponds to either a single fraction of radiotherapy (typical total dose is ≥10 Gy) or accumulates over long-duration interplanetary missions. Serum, marrow, and mineralized tissue were harvested 4 h—7 days later. Gamma irradiation caused a prompt (2.6-fold within 4 h) and persistent (peaking at 4.1-fold within 1 day) rise in the expression of the obligate osteoclastogenic cytokine, receptor activator of nuclear factor kappa-B ligand (Rankl), within marrow cells over controls. Similarly, Rankl expression peaked in marrow cells within 3 days of iron exposure (9.2-fold). Changes in Rankl expression induced by gamma irradiation preceded and overlapped with a rise in expression of other pro-osteoclastic cytokines in marrow (eg, monocyte chemotactic protein-1 increased by 11.9-fold, and tumor necrosis factor-alpha increased by 1.7-fold over controls). The ratio, Rankl/Opg, in marrow increased by 1.8-fold, a net pro-resorption balance. In the marrow, expression of the antioxidant transcription factor, Nfe2l2, strongly correlated with expression levels of Nfatc1, Csf1, Tnf, and Rankl. Radiation exposure increased a serum marker of bone resorption (tartrate-resistant acid phosphatase) and led to cancellous bone loss (16% decrement after 1 week). Finally, we conclude that total body irradiation (gamma or heavy-ion) caused temporal elevations in the concentrations of specific genes expressed within marrow and mineralized tissue related to bone resorption, including select cytokines that lead to osteoclastogenesis and elevated resorption; this is likely to account for rapid and progressive deterioration of cancellous microarchitecture following exposure to ionizing radiation.},
doi = {10.1089/jir.2014.0152},
journal = {Journal of Interferon & Cytokine Research},
number = 6,
volume = 35,
place = {United States},
year = {Tue Mar 03 00:00:00 EST 2015},
month = {Tue Mar 03 00:00:00 EST 2015}
}

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