Bone destruction is the major pathological process in many bone metabolic diseases and is a result of increased osteoclast formation and bone resorption. The liver X receptors (␣,␤), important regulators of cholesterol metabolism and inflammatory signaling, have recently been observed to play a role in both physiological and pathological bone turnover. However, the relationship between liver X receptors (LXR) and osteoclast differentiation/formation remains unknown. Here, we report that the LXR ligand GW3965 is able to clearly and potently inhibit the formation of mature osteoclasts from receptor activator of nuclear factor B ligand (RANKL)-stimulated human and murine osteoclast precursors. This results in a significant inhibition of bone resorption. We observed that GW3965 significantly inhibited expression of the osteoclast markers tartrateresistant acid phosphatase, cathepsin K, osteoclast-associated receptor (OSCAR), and calcitonin receptor, appearing to act in an NFATc1/p38/microphthalmia-associated transcription factor (MITF)-dependent mechanism, independently of receptor activator of nuclear factor B or c-Fos and not directly involving the NFB pathways. GW3965 was less effective in RAW264.7 monocyte/macrophage cells, which are more committed into the osteoclast lineage. Also, GW3965 seemed to act differently depending on the source of the progenitor cells as it had no effect on calvarial osteoclasts, compared with marrow or bloodderived monocytes. As these effects were abolished in osteoclast precursors derived from LXR␤ ؊/؊ mice, we suggest that GW3965 acts via an LXR␤-dependent mechanism. Taken together, our results suggest that the LXR can act as an important inhibitor of RANKL-mediated osteoclast differentiation.Bone remodeling occurs continuously throughout life to maintain bone quality in response to mechanical stress and hormonal regulation. To retain a normal bone mass, bone is resorbed by osteoclasts, and new bone matrix is deposited by osteoblasts in a tightly coupled process. Imbalances in this process can lead to excessive resorption by the osteoclasts and increased bone fragility, as observed in many common skeletal diseases (osteoporosis, metastatic bone disease, and Paget disease of bone) (1, 2). Osteoclasts are multinucleated giant cells derived from the pluripotent hematopoietic stem cell lineage. Differentiation of the precursor cells into the osteoclast lineage is principally regulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of NFB ligand (RANKL) 2 (3). Binding of RANKL to its receptor RANK activates different signaling cascades (NFB, MAPK, and Ca 2ϩ oscillation/calcineurin) to induce nuclear factor of activated T cells c1 (NFATc1), the key transcription factor in osteoclastogenesis (4, 5). NFATc1 in turn induces the transcription of osteoclast-specific genes, including tartrate-resistant acid phosphatase (TRAP/acp5), cathepsin K (ctsk), osteoclast-associated receptor (oscar), and calcitonin receptor (calcr) (6).The liver X receptors, LXR␣ and LXR␤, are me...

Bacterial-induced bone diseases, such as periodontitis and osteomyelitis, are chronic inflammatory diseases characterized by increased bone destruction as a result of enhanced osteoclastogenesis. The LXRα and -β are important modulators of inflammatory signaling and can potently inhibit RANKL-induced osteoclast differentiation. Here, we investigated the effects of the LXR agonist GW3965 on LPS-induced osteoclast differentiation. Mouse BMMs primed with RANKL for 24 h, then exposed to LPS in the presence of GW3965 for 4 days, formed significantly fewer and smaller TRAP(+)-multinucleated osteoclasts with reduced expression of osteoclast markers (Acp5, Ctsk, Mmp-9, Dc-stamp, and Itgβ3), along with inhibition of actin ring development. GW3965 was able to repress proinflammatory cytokine (TNF-α, IL-1β, IL-6, and IL-12p40) expression in BMMs exposed to LPS alone; however, once BMMs entered the osteoclast lineage following RANKL priming, GW3965 no longer inhibited cytokine expression. The inhibitory action of GW3965 involved the Akt pathway but seemed to be independent of MAPKs (p38, ERK, JNK) and NF-κB signaling. GW3965 acted in a LXRβ-dependent mechanism, as osteoclast differentiation was not inhibited in BMMs derived from LXRβ-/- mice. Finally, activation of LXR also inhibited differentiation in LPS-exposed mouse RAW264.7 cells. In conclusion, GW3965 acts through LXRβ to potently inhibit osteoclast differentiation from RANKL-primed BMMs in a LPS environment. In this respect, activation of the LXR could have a beneficial, therapeutic effect in the prevention of bacterial-induced bone erosion.

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