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Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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The steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and intestine where they function as xenobiotic sensors. In addition to its role as a xenobiotic sensor, previous studies in our laboratories and elsewhere have identified a role for SXR/PXR as a mediator of bone homeostasis. Here, we report that systemic deletion of PXR results in marked osteopenia with mechanical fragility in female mice as young as 4 months old. Bone mineral density (BMD) of PXR knockout (PXRKO) mice was significantly decreased compared with the BMD of wild-type (WT) mice. Micro-computed tomography analysis of femoral trabecular bones revealed that the three-dimensional bone volume fraction of PXRKO mice was markedly reduced compared with that of WT mice. Histomorphometrical analysis of the trabecular bones in the proximal tibia showed a remarkable reduction in bone mass in PXRKO mice. As for bone turnover of the trabecular bones, bone formation is reduced, whereas bone resorption is enhanced in PXRKO mice. Histomorphometrical analysis of femoral cortical bones revealed a larger cortical area in WT mice than that in PXRKO mice. WT mice had a thicker cortical width than PXRKO mice. Three-point bending test revealed that these morphological phenotypes actually caused mechanical fragility. Lastly, serum levels of phosphate, calcium, and alkaline phosphatase were unchanged in PXRKO mice compared with WT. Consistent with our previous results, we conclude that SXR/PXR promotes bone formation and suppresses bone resorption thus cementing a role for SXR/PXR as a key regulator of bone homeostasis.
