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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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Percent of the marrow space (mean ±SEM) occupied by hematopoietic precursors in intact control (I−R) and irradiated (I+R) mice estimated by visual inspection by a board certified veterinary clinical pathologist (LS) employing standard protocols.Radiation caused marked hypocellularity of the hematopoietic components of the marrow by Day 3, with significant increases but still very low hematopoietic activity on Day 8 and marked but still incomplete recovery of hematopoietic activity with normal precursor maturation at Day 30. There were no changes over time in non-irradiated animals. Two-way ANOVA with Tukey's post-tests: * Irradiated mice had significantly lower cellularity than control mice of the same day, p<0.0001, † Cellularity of irradiated mice increased significantly from Day 3 through Day 30, p: 0.0292 – <0.0001.
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pone-0042668-g003: Percent of the marrow space (mean ±SEM) occupied by hematopoietic precursors in intact control (I−R) and irradiated (I+R) mice estimated by visual inspection by a board certified veterinary clinical pathologist (LS) employing standard protocols.Radiation caused marked hypocellularity of the hematopoietic components of the marrow by Day 3, with significant increases but still very low hematopoietic activity on Day 8 and marked but still incomplete recovery of hematopoietic activity with normal precursor maturation at Day 30. There were no changes over time in non-irradiated animals. Two-way ANOVA with Tukey's post-tests: * Irradiated mice had significantly lower cellularity than control mice of the same day, p<0.0001, † Cellularity of irradiated mice increased significantly from Day 3 through Day 30, p: 0.0292 – <0.0001.

Mentions: In ovary-intact mice, we established that exposure to radiation resulted in marked hypocellularity of the hematopoietic components of the marrow by Day 3 (mean = 3.2%), with considerable recovery but still very low hematopoietic activity on Day 8 (mean = 12.8%, p = 0.0292 when comparing to Day 3) and marked but still incomplete recovery of hematopoietic activity with normal precursor maturation at Day 30 (mean = 72%, p<0.0001 when comparing to both Day3 and Day 8) (See Figure 3). Over the same time course, there was no change in hematopoietic cellularity in the I−R mice (mean = 95.4%, 94.6% and 96.2% for Day 3, 8 and 30, respectively) (Figure 3). As expected, megakaryocyte numbers were significantly depressed by radiation exposure on Days 3 (median scale = −3) and 8 (median scale = −3), with a trend towards ongoing suppression on Day 30 (median scale = −1) (Table 1). Although too few hematopoietic precursors were available for interpretation in the markedly hypocellular Day 3 post-irradiation marrow, the recovery phase was accompanied by significantly increased myeloid to erythroid ratios (median scale = 2 on Day 8 and = 1 on Day 30) characterized by persistent erythroid hypoplasia (Table 1). Radiation resulted in concurrent vascular abnormalities in the marrow space, including moderate to marked sinusoidal dilation and venous congestion that were mostly resolved by Day 30, and transient edema on Day 8 (Table 2). Endosteal lining cells were transiently plump in 4/5 mice on Day 3 only. Increased hemosiderin (iron pigment) was observed in 3/5 irradiated mice and fibrosis in 2/5 irradiated mice on Day 30 only. These changes were not associated with evidence of inflammation in the marrow space.


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)

Percent of the marrow space (mean ±SEM) occupied by hematopoietic precursors in intact control (I−R) and irradiated (I+R) mice estimated by visual inspection by a board certified veterinary clinical pathologist (LS) employing standard protocols.Radiation caused marked hypocellularity of the hematopoietic components of the marrow by Day 3, with significant increases but still very low hematopoietic activity on Day 8 and marked but still incomplete recovery of hematopoietic activity with normal precursor maturation at Day 30. There were no changes over time in non-irradiated animals. Two-way ANOVA with Tukey's post-tests: * Irradiated mice had significantly lower cellularity than control mice of the same day, p<0.0001, † Cellularity of irradiated mice increased significantly from Day 3 through Day 30, p: 0.0292 – <0.0001.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042668-g003: Percent of the marrow space (mean ±SEM) occupied by hematopoietic precursors in intact control (I−R) and irradiated (I+R) mice estimated by visual inspection by a board certified veterinary clinical pathologist (LS) employing standard protocols.Radiation caused marked hypocellularity of the hematopoietic components of the marrow by Day 3, with significant increases but still very low hematopoietic activity on Day 8 and marked but still incomplete recovery of hematopoietic activity with normal precursor maturation at Day 30. There were no changes over time in non-irradiated animals. Two-way ANOVA with Tukey's post-tests: * Irradiated mice had significantly lower cellularity than control mice of the same day, p<0.0001, † Cellularity of irradiated mice increased significantly from Day 3 through Day 30, p: 0.0292 – <0.0001.
Mentions: In ovary-intact mice, we established that exposure to radiation resulted in marked hypocellularity of the hematopoietic components of the marrow by Day 3 (mean = 3.2%), with considerable recovery but still very low hematopoietic activity on Day 8 (mean = 12.8%, p = 0.0292 when comparing to Day 3) and marked but still incomplete recovery of hematopoietic activity with normal precursor maturation at Day 30 (mean = 72%, p<0.0001 when comparing to both Day3 and Day 8) (See Figure 3). Over the same time course, there was no change in hematopoietic cellularity in the I−R mice (mean = 95.4%, 94.6% and 96.2% for Day 3, 8 and 30, respectively) (Figure 3). As expected, megakaryocyte numbers were significantly depressed by radiation exposure on Days 3 (median scale = −3) and 8 (median scale = −3), with a trend towards ongoing suppression on Day 30 (median scale = −1) (Table 1). Although too few hematopoietic precursors were available for interpretation in the markedly hypocellular Day 3 post-irradiation marrow, the recovery phase was accompanied by significantly increased myeloid to erythroid ratios (median scale = 2 on Day 8 and = 1 on Day 30) characterized by persistent erythroid hypoplasia (Table 1). Radiation resulted in concurrent vascular abnormalities in the marrow space, including moderate to marked sinusoidal dilation and venous congestion that were mostly resolved by Day 30, and transient edema on Day 8 (Table 2). Endosteal lining cells were transiently plump in 4/5 mice on Day 3 only. Increased hemosiderin (iron pigment) was observed in 3/5 irradiated mice and fibrosis in 2/5 irradiated mice on Day 30 only. These changes were not associated with evidence of inflammation in the marrow space.

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