Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling
María P. Menéndez-Gutiérrez, Tamás Rőszer, Lucía Fuentes, Vanessa Núñez, Amelia Escolano, Juan Miguel Redondo, Nora De Clerck, Daniel Metzger, Annabel F. Valledor, Mercedes Ricote
María P. Menéndez-Gutiérrez, Tamás Rőszer, Lucía Fuentes, Vanessa Núñez, Amelia Escolano, Juan Miguel Redondo, Nora De Clerck, Daniel Metzger, Annabel F. Valledor, Mercedes Ricote
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Research Article Bone biology

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

María P. Menéndez-Gutiérrez, Tamás Rőszer, Lucía Fuentes, Vanessa Núñez, Amelia Escolano, Juan Miguel Redondo, Nora De Clerck, Daniel Metzger, Annabel F. Valledor, Mercedes Ricote

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Figure 7

Pharmacological activation of RXR/LXR heterodimers blocks osteoclast differentiation through upregulation of MAFB.

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Pharmacological activation of RXR/LXR heterodimers blocks osteoclast dif...
(A and B) In vitro osteoclast differentiation from WT and RXR-KO bone marrow cells, treated with vehicle (control) or LG268. (A) Representative mature osteoclasts identified as multinucleated TRAP+ cells. Scale bars: 100 μm. (B) Mafb mRNA expression over a time course of osteoclast differentiation. **P < 0.01; ***P < 0.001, compared with WT. ###P < 0.001 for RXR-KO + LG268 compared with WT + LG268. (C and D) Mafb mRNA expression in WT and RXR-KO or Lxr-KO osteoclast progenitors treated with vehicle (C) or ligands for RXR (LG268) and LXR (T1317). *P < 0.05; **P < 0.01; ***P < 0.001, compared with WT vehicle-treated cells (C) (paired 2-tailed Student’s t test), ###P < 0.001 versus the equivalent treatment in WT cells (unpaired 2-tailed Student’s t test). (E) MAFB protein in WT and RXR-KO or Lxr-KO osteoclast progenitors treated with vehicle or ligands for RXR (LG268) and LXR (T1317); representative of 3 independent experiments. (F) Luciferase reporter assay in RAW264.7 cells transfected with RXRα and LXRβ or CMX empty vector together with a reporter vector containing 1.5 kb of the Mafb promoter. Data are presented relative to values obtained with the vehicle-treated Mafb reporter in the absence of RXRα and LXRβ. **P < 0.01; ***P < 0.001. Data are presented as mean ± SEM (n = 3 per group); statistical comparisons were made by paired (D and F) or unpaired (B) 2-tailed Student’s t test.