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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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3-D illustration of interrelationships among the three tissue components of bone and marrow: hemopoietic component measured by cellularity, stromal damage component measured by marrow fat or adipose content, and osseous component measured by the cancellous bone BV/TV%.Cumulative increases in marrow fat after irradiation, in the absence of ovarian function (10 fold) was not reflected by equivalent losses of either cancellous bone or hematopoietic cellularity. The proportionality of changes in these tissue components were maintained among irradiated intact mice.
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pone-0042668-g005: 3-D illustration of interrelationships among the three tissue components of bone and marrow: hemopoietic component measured by cellularity, stromal damage component measured by marrow fat or adipose content, and osseous component measured by the cancellous bone BV/TV%.Cumulative increases in marrow fat after irradiation, in the absence of ovarian function (10 fold) was not reflected by equivalent losses of either cancellous bone or hematopoietic cellularity. The proportionality of changes in these tissue components were maintained among irradiated intact mice.

Mentions: It should be noted that 30 days after irradiation was equal to 87 days post OVX in the present study (Figure 1). Since bone surfaces are generally quiescent following ovariectomy with time [33], marrow may be expected to respond to radiation to a greater degree when compared with bone, since rapidly dividing cells are more radiosensitive (demonstrated by Figures 3 and 4). Additionally, the ovary intact animals may exhibit more tightly coordinated interactions between the marrow milieu and the adjacent bone, while the lack of ovarian hormones uncouples the two resulting in disproportionate effects between these tissue envelopes as illustrated by Figure 5. New evidence demonstrates more independent regulation of bone and fat under some circumstances [34]. Differential radiosensitivity of the constituent cell populations should be investigated further by more extensive studies in bone and isolated marrow cell survivability.


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)

3-D illustration of interrelationships among the three tissue components of bone and marrow: hemopoietic component measured by cellularity, stromal damage component measured by marrow fat or adipose content, and osseous component measured by the cancellous bone BV/TV%.Cumulative increases in marrow fat after irradiation, in the absence of ovarian function (10 fold) was not reflected by equivalent losses of either cancellous bone or hematopoietic cellularity. The proportionality of changes in these tissue components were maintained among irradiated intact mice.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042668-g005: 3-D illustration of interrelationships among the three tissue components of bone and marrow: hemopoietic component measured by cellularity, stromal damage component measured by marrow fat or adipose content, and osseous component measured by the cancellous bone BV/TV%.Cumulative increases in marrow fat after irradiation, in the absence of ovarian function (10 fold) was not reflected by equivalent losses of either cancellous bone or hematopoietic cellularity. The proportionality of changes in these tissue components were maintained among irradiated intact mice.
Mentions: It should be noted that 30 days after irradiation was equal to 87 days post OVX in the present study (Figure 1). Since bone surfaces are generally quiescent following ovariectomy with time [33], marrow may be expected to respond to radiation to a greater degree when compared with bone, since rapidly dividing cells are more radiosensitive (demonstrated by Figures 3 and 4). Additionally, the ovary intact animals may exhibit more tightly coordinated interactions between the marrow milieu and the adjacent bone, while the lack of ovarian hormones uncouples the two resulting in disproportionate effects between these tissue envelopes as illustrated by Figure 5. New evidence demonstrates more independent regulation of bone and fat under some circumstances [34]. Differential radiosensitivity of the constituent cell populations should be investigated further by more extensive studies in bone and isolated marrow cell survivability.

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