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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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Schematic representation of bone and marrow.A. region of interest in sagittal view of a normal control mouse. B. Sagittal section of bone marrow from an intact mouse 8 days post-irradiation. Note the areas of congestion and sinusoidal dilation characterized by increased density of red blood cell within the expanded vascular spaces; also present are areas of edema characterized by increased volume of pale pink fluid in the interstitial spaces. C. Sagittal sections of bone marrow 30 days after irradiation in intact (C1) and OVX (C2) mice. Note the more intensely purple areas indicative of higher hematopoietic activity in C1 compared with C2, as well as expanded adipose in C2 compared with C1.
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pone-0042668-g002: Schematic representation of bone and marrow.A. region of interest in sagittal view of a normal control mouse. B. Sagittal section of bone marrow from an intact mouse 8 days post-irradiation. Note the areas of congestion and sinusoidal dilation characterized by increased density of red blood cell within the expanded vascular spaces; also present are areas of edema characterized by increased volume of pale pink fluid in the interstitial spaces. C. Sagittal sections of bone marrow 30 days after irradiation in intact (C1) and OVX (C2) mice. Note the more intensely purple areas indicative of higher hematopoietic activity in C1 compared with C2, as well as expanded adipose in C2 compared with C1.

Mentions: Bone microarchitecture of mice was analyzed with a microCT Scanner (μCT 35, Cone-Beam microCT, Scanco Medical, Switzerland). The distal femoral metaphysis was scanned within a region of 0.3–1.0 mm from the growth plate in order to avoid the primary spongiosa, with a slice thickness of 7 µm resolution (100 slices) at 70 kVp. Using the manufacturer's software, cancellous bone regions of interest (ROIs) were drawn (see Figure 2 A). The cancellous bone is composed of trabecular bone matrix and marrow. The cancellous bone volume fraction (BV/TV %; i.e. the ratio of the segmented trabecular bone volume to the total tissue volume of the region of interest) of the ROI was estimated.


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)

Schematic representation of bone and marrow.A. region of interest in sagittal view of a normal control mouse. B. Sagittal section of bone marrow from an intact mouse 8 days post-irradiation. Note the areas of congestion and sinusoidal dilation characterized by increased density of red blood cell within the expanded vascular spaces; also present are areas of edema characterized by increased volume of pale pink fluid in the interstitial spaces. C. Sagittal sections of bone marrow 30 days after irradiation in intact (C1) and OVX (C2) mice. Note the more intensely purple areas indicative of higher hematopoietic activity in C1 compared with C2, as well as expanded adipose in C2 compared with C1.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412808&req=5

pone-0042668-g002: Schematic representation of bone and marrow.A. region of interest in sagittal view of a normal control mouse. B. Sagittal section of bone marrow from an intact mouse 8 days post-irradiation. Note the areas of congestion and sinusoidal dilation characterized by increased density of red blood cell within the expanded vascular spaces; also present are areas of edema characterized by increased volume of pale pink fluid in the interstitial spaces. C. Sagittal sections of bone marrow 30 days after irradiation in intact (C1) and OVX (C2) mice. Note the more intensely purple areas indicative of higher hematopoietic activity in C1 compared with C2, as well as expanded adipose in C2 compared with C1.
Mentions: Bone microarchitecture of mice was analyzed with a microCT Scanner (μCT 35, Cone-Beam microCT, Scanco Medical, Switzerland). The distal femoral metaphysis was scanned within a region of 0.3–1.0 mm from the growth plate in order to avoid the primary spongiosa, with a slice thickness of 7 µm resolution (100 slices) at 70 kVp. Using the manufacturer's software, cancellous bone regions of interest (ROIs) were drawn (see Figure 2 A). The cancellous bone is composed of trabecular bone matrix and marrow. The cancellous bone volume fraction (BV/TV %; i.e. the ratio of the segmented trabecular bone volume to the total tissue volume of the region of interest) of the ROI was estimated.

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