Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss.
Osteoporosis is characterized by enhanced differentiation of bone-resorbing osteoclasts, resulting in a rapid loss of functional trabecular bone. Bone-forming osteoblasts and osteoblast-derived osteocytes perform a key role in the regulation of osteoclast development by providing both the pro-osteoclastogenic cytokine receptor activator of NF-κB ligand (RANKL) and its natural decoy receptor osteoprotegerin (OPG). By regulating the RANKL/OPG ratio, osteoblasts hence determine the rate of both osteoclast differentiation and bone turnover. Here, we describe a novel role for liver X receptors (LXRs) during the crosstalk of bone-forming osteoblasts and bone-resorbing osteoclasts. By using a system of osteoblast/osteoclast cocultures, we identify LXRs as regulator of RANKL expression and the RANKL/OPG ratio in osteoblasts. Activation of LXRs drastically reduced the RANKL/OPG ratio and interfered with osteoblast-mediated osteoclast differentiation in vitro. During an ovariectomy (OVX)-induced model of postmenopausal osteoporosis, the application of an LXR agonist shifted the RANKL/OPG ratio in vivo, ameliorated the enhanced osteoclast differentiation, and provided complete protection from OVX-induced bone loss. These results reveal an unexpected involvement of LXRs in the regulation of bone turnover and highlight a potential role for LXRs as novel targets in the treatment of osteoporosis and related diseases.
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Arnd
A
Kleyer
Carina
C
Scholtysek
Edith
E
Bottesch
Ulrike
U
Hillienhof
Christian
C
Beyer
Jörg Hw
JH
Distler
Jan P
JP
Tuckermann
Georg
G
Schett
Gerhard
G
Krönke
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001862:Bone Resorption / Q000188:drug therapy; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000502:physiology* / Q000627:therapeutic use; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology*; D010024:Osteoporosis / Q000188:drug therapy; D053244:Osteoprotegerin / Q000378:metabolism; D010052:Ovariectomy; D053245:RANK Ligand / Q000378:metabolism
D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D053244:Osteoprotegerin; D053245:RANK Ligand