Ionizing Radiation Stimulates Expression of Pro-Osteoclastogenic Genes in Marrow and Skeletal Tissue.
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 ((137)Cs, 0.8 Gy/min) or heavy ions ((56)Fe, 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). 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.
Bone and Signaling Laboratory , Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.
Joshua S
JS
Alwood
Bone and Signaling Laboratory , Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.
Mohammad
M
Shahnazari
Bone and Signaling Laboratory , Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.
Betsabel
B
Chicana
Bone and Signaling Laboratory , Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.
A S
AS
Schreurs
Bone and Signaling Laboratory , Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.
Akhilesh
A
Kumar
Bone and Signaling Laboratory , Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.
Alana
A
Bartolini
Bone and Signaling Laboratory , Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.
Yasaman
Y
Shirazi-Fard
Bone and Signaling Laboratory , Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.
Ruth K
RK
Globus
D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D001862:Bone Resorption / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays / Q000009:adverse effects*; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071681:Tartrate-Resistant Acid Phosphatase; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014916:Whole-Body Irradiation
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C495636:Nfe2l2 protein, mouse; D053244:Osteoprotegerin; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase