title: Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling.
abstract: Osteoclasts are bone-resorbing cells that are important for maintenance of bone remodeling and mineral homeostasis. Regulation of osteoclast differentiation and activity is important for the pathogenesis and treatment of diseases associated with bone loss. Here, we demonstrate that retinoid X receptors (RXRs) are key elements of the transcriptional program of differentiating osteoclasts. Loss of RXR function in hematopoietic cells resulted in formation of giant, nonresorbing osteoclasts and increased bone mass in male mice and protected female mice from bone loss following ovariectomy, which induces osteoporosis in WT females. The increase in bone mass associated with RXR deficiency was due to lack of expression of the RXR-dependent transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B (MAFB) in osteoclast progenitors. Evaluation of osteoclast progenitor cells revealed that RXR homodimers directly target and bind to the Mafb promoter, and this interaction is required for proper osteoclast proliferation, differentiation, and activity. Pharmacological activation of RXRs inhibited osteoclast differentiation due to the formation of RXR/liver X receptor (LXR) heterodimers, which induced expression of sterol regulatory element binding protein-1c (SREBP-1c), resulting in indirect MAFB upregulation. Our study reveals that RXR signaling mediates bone homeostasis and suggests that RXRs have potential as targets for the treatment of bone pathologies such as osteoporosis.
authors.forename: María P
authors.initials: MP
authors.lastname: Menéndez-Gutiérrez
authors.forename: Tamás
authors.initials: T
authors.lastname: Rőszer
authors.forename: Lucía
authors.initials: L
authors.lastname: Fuentes
authors.forename: Vanessa
authors.initials: V
authors.lastname: Núñez
authors.forename: Amelia
authors.initials: A
authors.lastname: Escolano
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
authors.forename: Nora
authors.initials: N
authors.lastname: De Clerck
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Annabel F
authors.initials: AF
authors.lastname: Valledor
authors.forename: Mercedes
authors.initials: M
authors.lastname: Ricote
mesh_terms: D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D005260:Female; D000071518:Liver X Receptors; D051258:MafB Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization / Q000502:physiology*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000071518:Liver X Receptors; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D057093:Orphan Nuclear Receptors; D047488:Retinoid X Receptors; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1