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. 2017 Apr 12:7:46325.
doi: 10.1038/srep46325.

Bone Marrow Adipose Tissue Deficiency Increases Disuse-Induced Bone Loss in Male Mice

Jessica A Keune  1 , Carmen P Wong  1 , Adam J Branscum  2 , Urszula T Iwaniec  1   3 , Russell T Turner  1   3
Affiliations

Bone Marrow Adipose Tissue Deficiency Increases Disuse-Induced Bone Loss in Male Mice

Jessica A Keune et al. Sci Rep. .

Abstract

Bone marrow adipose tissue (MAT) is negatively associated with bone mass. Since osteoblasts and adipocytes are derived from the same precursor cells, adipocyte differentiation may occur at the expense of osteoblast differentiation. We used MAT-deficient KitW/W-v (MAT-) mice to determine if absence of MAT reduced bone loss in hindlimb-unloaded (HU) mice. Male MAT- and wild-type (WT) mice were randomly assigned to a baseline, control or HU group (n = 10 mice/group) within each genotype and HU groups unloaded for 2 weeks. Femurs were evaluated using micro-computed tomography, histomorphometry and targeted gene profiling. MAT- mice had a greater reduction in bone volume fraction after HU than did WT mice. HU MAT- mice had elevated cancellous bone formation and resorption compared to other treatment groups as well as a unique profile of differentially expressed genes. Adoptive transfer of WT bone marrow-derived hematopoietic stem cells reconstituted c-kit but not MAT in KitW/W-v mice. The MAT- WT → KitW/W-v mice lost cancellous bone following 2 weeks of HU. In summary, results from this study suggest that MAT deficiency was not protective, and was associated with exaggerated disuse-induced cancellous bone loss.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Effects of genotype, hindlimb unloading (HU) and their interaction on (a) body weight, (b) white adipose tissue weight, (c) seminal vesicle weight and (d) blood glucose. Two-way ANOVA: a, different from control mice within genotype. P-values significant at P ≤ 0.05. Mean ± SEM.
Figure 2
Figure 2. Effects of genotype, hindlimb unloading (HU) and their interaction on cancellous bone microarchitecture in the distal femur metaphysis.
Shown are (a) cancellous bone volume fraction, (b) connectivity density, (c) trabecular number, (d) trabecular thickness, (e) trabecular spacing. Two-way ANOVA: a, different from control mice within genotype; b, different from WT mice within treatment. P-values significant at P ≤ 0.05. Mean ± SEM. Representative uCT images are show from (f) WT control, (g) WT HU, (h) MAT- control, and (i) MAT- HU mice. Images compiled by JAK.
Figure 3
Figure 3. Effects of genotype, hindlimb unloading (HU) and their interaction on marrow adiposity and cancellous bone histomorphometry in the distal femur metaphysis.
Shown are (a) bone marrow adiposity, (b) adipocyte density, (c) adipocyte size, (d) image showing presence of adipocytes in WT mouse, (e) image showing absence of adipocytes in MAT- mouse, (f) osteoblast perimeter, (g) osteoclast perimeter, (h) mineralizing perimeter, (i) mineral apposition rate, and (j) bone formation rate. Two-way ANOVA: a, different from control mice within genotype; b, different from WT mice within treatment. P-values significant at P ≤ 0.05. Mean ± SEM. Image scale is 500 μm at 4x. Images taken by JAK.
Figure 4
Figure 4. Relative expression of genes relating to osteoblast and osteoclast differentiation and function normalized to Gapdh.
WT CTL mice were used to compare the effects of HU (red circle; 10 genes differentially expressed), MAT deficiency (green circle; 5 genes differentially expressed), and MAT deficiency after HU (blue circle; 21 genes differentially expressed).
Figure 5
Figure 5. GFP-positive cells in WT control (no adoptive transfer) and KitW/W−v mice 8 weeks post adoptive transfer showing successful transfer of GFP-labeled HSC.
Mean ± SEM.
Figure 6
Figure 6
Images of histological sections from (a) WT→Kitw/w−v control and (b) WT→Kitw/w−v HU mice showing absence of adipocytes following adoptive transfer of WT HSC. Scale is 500 μm at 4x. Images taken by JAK.
Figure 7
Figure 7. Effects of hindlimb unloading (HU) following adoptive transfer (WT→Kitw/w−v) on cancellous bone microarchitecture in the distal femur metaphysis.
Shown are (a) cancellous bone volume fraction, (b) connectivity density, (c) trabecular number, (d) trabecular thickness and (e) trabecular spacing. T-test: P-values significant at P ≤ 0.05. Mean ± SEM.
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