The liver × receptor (α,β) is responsible for regulating cholesterol homeostasis in cells. However, our studies using the LXRα^−/−, LXRβ^−/−, and LXRα^−/−β^−/− mice show that both LXRα and β are also important for bone turnover, mainly by regulating osteoclast differentiation/activity.

Introduction: The liver × receptors (α,β) are primarily responsible for regulating cholesterol homeostasis within cells and the whole body. However, as recent studies show that the role for this receptor is expanding, we studied whether the LXRs could be implicated in bone homeostasis and development.

Materials and Methods: pQCT was performed on both male and female LXRα^−/−, LXRβ^−/−, LXRα^−/−β^−/−, and WT mice at 4 months and 1 year of age. Four‐month‐old female mice were additionally analyzed with reference to qPCR, immunohistochemistry, histomorphometry, transmission electron microscopy, and serum bone turnover markers.

Results: At the mRNA level, LXRβ was more highly expressed than LXRα in both whole long bones and differentiating osteoblast‐like MC3T3‐E1 and osteoclast‐like RAW 264.7 cells. Four‐month‐old female LXRα^−/− mice had a significant increase in BMD because of an increase in all cortical parameters. No difference was seen regarding trabecular BMD. Quantitative histomorphometry showed that these mice had significantly more endosteal osteoclasts in the cortical bone; however, these cells appeared less active than normal cells as suggested by a significant reduction in serum levels of cross‐linked carboxyterminal telopeptides of type I collagen (CTX) and a reduction in bone TRACP activity. Conversely, the female LXRβ^−/− mice exhibited no change in BMD, presumably because a significant decline in the number of the trabecular osteoclasts was compensated for by an increase in the expression of the osteoclast markers cathepsin K and TRACP. These mice also had a significant decrease in serum CTX, suggesting decreased bone resorption; however, in addition presented with an increase in the expression of osteoblast associated genes, bone formation markers, and serum leptin levels.

Conclusions: Our findings show that both LXRs influence cellular function within the bone, with LXRα having an impact on osteoclast activity, primarily in cortical bone, whereas LXRβ modulates trabecular bone turnover.