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The influence of therapeutic radiation on the patterns of bone marrow in ovary-intact and ovariectomized mice.

Hui SK, Sharkey L, Kidder LS, Zhang Y, Fairchild G, Coghill K, Xian CJ, Yee D - PLoS ONE (2012)

Bottom Line: Ovariectomy alone did not significantly reduce marrow cellularity in non-irradiated mice (OVX-R vs.The synergistic effect was also apparent in the reduction of hematopoietic marrow cellularity (p = 0.0661); however it was absent in BV/TV% changes (p = 0.2520).Interestingly compared with OVX mice, intact mice demonstrated double the reduction in hematopoietic cellularity and a tenfold greater degree of bone loss for a given unit of expansion in marrow fat.

View Article: PubMed Central - PubMed

Affiliation: Department of Therapeutic Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America. huixx019@umn.edu

ABSTRACT

Background: The functional components of bone marrow (i.e., the hematopoietic and stromal populations) and the adjacent bone have traditionally been evaluated incompletely as distinct entities rather than the integrated system. We perturbed this system in vivo using a medically relevant radiation model in the presence or absence of ovarian function to understand integrated tissue interaction.

Methodology/principal findings: Ovary-intact and ovariectomized mice underwent either no radiation or single fractional 16 Gy radiation to the caudal skeleton (I ± R, OVX ± R). Marrow fat, hematopoietic cellularity, and cancellous bone volume fraction (BV/TV %) were assessed. Ovariectomy alone did not significantly reduce marrow cellularity in non-irradiated mice (OVX-R vs. I-R, p = 0.8445) after 30 days; however it impaired the hematopoietic recovery of marrow following radiation exposure (OVX+R vs. I+R, p = 0.0092). The combination of radiation and OVX dramatically increases marrow fat compared to either factor alone (p = 0.0062). The synergistic effect was also apparent in the reduction of hematopoietic marrow cellularity (p = 0.0661); however it was absent in BV/TV% changes (p = 0.2520). The expected inverse relationship between marrow adiposity vs. hematopoietic cellularity and bone volume was observed. Interestingly compared with OVX mice, intact mice demonstrated double the reduction in hematopoietic cellularity and a tenfold greater degree of bone loss for a given unit of expansion in marrow fat.

Conclusions/significance: Ovariectomy prior to delivery of a clinically-relevant focal radiation exposure in mice, exacerbated post-radiation adipose accumulation in the marrow space but blunted bone loss and hematopoietic suppression. In the normally coupled homeostatic relationship between the bone and marrow domains, OVX appears to alter feedback mechanisms. Confirmation of this non-linear phenomenon (presumably due to differential radiosensitivity) and demonstration of the mechanism of action is needed to provide strategies to diminish the effect of radiation on exposed tissues.

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Experimental Plan Schematic.Sixteen week old BALB/c mice were ovariectomized (OVX) and maintained in the vivarium for 57 days in order to attain skeletal hemostasis. Both intact (I) and OVX mice were then irradiated with 16Gy delivered to the caudal skeleton or maintained as controls. Groups of animals were euthanized at 3, 8, and 30 days post irradiation in order to perform histological evaluations of the distal femur; microCT measurements were conducted at the 30 day time point only.
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pone-0042668-g001: Experimental Plan Schematic.Sixteen week old BALB/c mice were ovariectomized (OVX) and maintained in the vivarium for 57 days in order to attain skeletal hemostasis. Both intact (I) and OVX mice were then irradiated with 16Gy delivered to the caudal skeleton or maintained as controls. Groups of animals were euthanized at 3, 8, and 30 days post irradiation in order to perform histological evaluations of the distal femur; microCT measurements were conducted at the 30 day time point only.

Mentions: Four groups of skeletally mature BALB/c female mice (16 weeks old) were used for this study. The schematic representation of the design of this study is described by Figure 1. The first experiment characterized the response of the hematopoietic space to a clinically relevant dose of radiation in intact female mice to establish the kinetics of hematopoietic recovery in the presence of normal ovarian function. The second experiment evaluated the response of bone and hematopoietic marrow space 30 days after radiation exposure in both ovary-intact (I) and ovariectomized (OVX) mice, which were utilized to mimic the clinical management of pre-menopausal and menopausal (spontaneous or induced) cancer patients undergoing radiation therapy (R), with appropriate controls. OVX mice were ovariectomized by the vendor 57 days prior to irradiation (Jackson Laboratory; Bar Harbor, ME). The day of radiation is designated Day 0. Mice were randomly divided into the following groups: 1) “I−R” (intact no radiation, n = 5, 5 and 7 sacrificed at day 3, 8 and 30; 2) “I+R” (intact irradiated, n = 5, 5 and 9 sacrificed at day 3, 8 and 30); 3) “OVX−R” (OVX no radiation, n = 7 sacrificed at day 30); and 4) “OVX+R” (OVX irradiated, n = 8 sacrificed at day 30). This study was approved by the University of Minnesota Institutional Animal Care and Use Committee (IACUC).


The influence of therapeutic radiation on the patterns of bone marrow in ovary-intact and ovariectomized mice.

Hui SK, Sharkey L, Kidder LS, Zhang Y, Fairchild G, Coghill K, Xian CJ, Yee D - PLoS ONE (2012)

Experimental Plan Schematic.Sixteen week old BALB/c mice were ovariectomized (OVX) and maintained in the vivarium for 57 days in order to attain skeletal hemostasis. Both intact (I) and OVX mice were then irradiated with 16Gy delivered to the caudal skeleton or maintained as controls. Groups of animals were euthanized at 3, 8, and 30 days post irradiation in order to perform histological evaluations of the distal femur; microCT measurements were conducted at the 30 day time point only.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412808&req=5

pone-0042668-g001: Experimental Plan Schematic.Sixteen week old BALB/c mice were ovariectomized (OVX) and maintained in the vivarium for 57 days in order to attain skeletal hemostasis. Both intact (I) and OVX mice were then irradiated with 16Gy delivered to the caudal skeleton or maintained as controls. Groups of animals were euthanized at 3, 8, and 30 days post irradiation in order to perform histological evaluations of the distal femur; microCT measurements were conducted at the 30 day time point only.
Mentions: Four groups of skeletally mature BALB/c female mice (16 weeks old) were used for this study. The schematic representation of the design of this study is described by Figure 1. The first experiment characterized the response of the hematopoietic space to a clinically relevant dose of radiation in intact female mice to establish the kinetics of hematopoietic recovery in the presence of normal ovarian function. The second experiment evaluated the response of bone and hematopoietic marrow space 30 days after radiation exposure in both ovary-intact (I) and ovariectomized (OVX) mice, which were utilized to mimic the clinical management of pre-menopausal and menopausal (spontaneous or induced) cancer patients undergoing radiation therapy (R), with appropriate controls. OVX mice were ovariectomized by the vendor 57 days prior to irradiation (Jackson Laboratory; Bar Harbor, ME). The day of radiation is designated Day 0. Mice were randomly divided into the following groups: 1) “I−R” (intact no radiation, n = 5, 5 and 7 sacrificed at day 3, 8 and 30; 2) “I+R” (intact irradiated, n = 5, 5 and 9 sacrificed at day 3, 8 and 30); 3) “OVX−R” (OVX no radiation, n = 7 sacrificed at day 30); and 4) “OVX+R” (OVX irradiated, n = 8 sacrificed at day 30). This study was approved by the University of Minnesota Institutional Animal Care and Use Committee (IACUC).

Bottom Line: Ovariectomy alone did not significantly reduce marrow cellularity in non-irradiated mice (OVX-R vs.The synergistic effect was also apparent in the reduction of hematopoietic marrow cellularity (p = 0.0661); however it was absent in BV/TV% changes (p = 0.2520).Interestingly compared with OVX mice, intact mice demonstrated double the reduction in hematopoietic cellularity and a tenfold greater degree of bone loss for a given unit of expansion in marrow fat.

View Article: PubMed Central - PubMed

Affiliation: Department of Therapeutic Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America. huixx019@umn.edu

ABSTRACT

Background: The functional components of bone marrow (i.e., the hematopoietic and stromal populations) and the adjacent bone have traditionally been evaluated incompletely as distinct entities rather than the integrated system. We perturbed this system in vivo using a medically relevant radiation model in the presence or absence of ovarian function to understand integrated tissue interaction.

Methodology/principal findings: Ovary-intact and ovariectomized mice underwent either no radiation or single fractional 16 Gy radiation to the caudal skeleton (I ± R, OVX ± R). Marrow fat, hematopoietic cellularity, and cancellous bone volume fraction (BV/TV %) were assessed. Ovariectomy alone did not significantly reduce marrow cellularity in non-irradiated mice (OVX-R vs. I-R, p = 0.8445) after 30 days; however it impaired the hematopoietic recovery of marrow following radiation exposure (OVX+R vs. I+R, p = 0.0092). The combination of radiation and OVX dramatically increases marrow fat compared to either factor alone (p = 0.0062). The synergistic effect was also apparent in the reduction of hematopoietic marrow cellularity (p = 0.0661); however it was absent in BV/TV% changes (p = 0.2520). The expected inverse relationship between marrow adiposity vs. hematopoietic cellularity and bone volume was observed. Interestingly compared with OVX mice, intact mice demonstrated double the reduction in hematopoietic cellularity and a tenfold greater degree of bone loss for a given unit of expansion in marrow fat.

Conclusions/significance: Ovariectomy prior to delivery of a clinically-relevant focal radiation exposure in mice, exacerbated post-radiation adipose accumulation in the marrow space but blunted bone loss and hematopoietic suppression. In the normally coupled homeostatic relationship between the bone and marrow domains, OVX appears to alter feedback mechanisms. Confirmation of this non-linear phenomenon (presumably due to differential radiosensitivity) and demonstration of the mechanism of action is needed to provide strategies to diminish the effect of radiation on exposed tissues.

Show MeSH
Related in: MedlinePlus