Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling
María P. Menéndez-Gutiérrez, … , Annabel F. Valledor, Mercedes Ricote
María P. Menéndez-Gutiérrez, … , Annabel F. Valledor, Mercedes Ricote
Published January 9, 2015
Citation Information: J Clin Invest. 2015;125(2):809-823. https://doi.org/10.1172/JCI77186.
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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 1

Increased bone mass and reduced osteoclast activity in 20-week-old RXR-KO male mice.

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Increased bone mass and reduced osteoclast activity in 20-week-old RXR-K...
(A and B) BMD and BMC measured by DEXA; BMC values are normalized to body weight (g/g). n = 8 mice per genotype. (C) Representative μCT images showing cortical bone of the femoral shaft and cortical bone thickness measured on μCT scans. n = 5 mice per genotype. (D) Histomorphometric analysis of the tibial end of the femur. BV/TV (%), relative trabecular bone volume; TbTh, trabecule thickness; TbSp, trabecule separation; TbN, trabecule number. n = 8 per genotype. (E) TRAP staining of the tibial end of the femur. bm, bone marrow; tb, trabecule; cb, cortical bone. Scale bars: 85 μm. (F and G) Osteoclast number (NOc/Bpm) (mm-1) and surface (OcS/Bs) (%) in femur sections, normalized to bone perimeter (Bpm) and bone surface (BS). n = 6 per genotype. (H) Representative TEM images of osteoclasts in the femur from 2 independent studies using 3 mice per genotype. bmx, bone matrix. Arrows show ruffled border; asterisks indicate the attachment zone. Scale bars: 5 μm. (I) Clinical chemistry of osteoclast activity. n = 9 (TRAP, DPD) and 6 (CTX) per genotype. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, compared with WT (unpaired 2-tailed Student’s t test).