Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling

Abstract

R e s e a R c h a R t i c l e8under this pathological condition, we induced estrogen deficiency by bilateral ovariectomy (OvX) in 20-week-old WT and RXR-KO mice and assessed bone loss over a further 8 weeks. Consistent with the lack of a skeletal phenotype in RXR-KO females (Supplemental Figure 3), age-and sex-matched sham-operated WT and RXR-KO mice showed no differences in bone architecture or osteoclast activity ( Figure 2). However, after OvX, loss of trabecular bone mass was significantly lower in RXR-KO mice (Figure 2, A-D). In WT mice, OvX led to a marked increase in osteoclast activity, shown by a rise in urine DPD and plasma CTX concentrations (Figure 2, E and F). In contrast, the increase in DPD and CTX concentrations was significantly lower in ovariectomized RXR-KO mice (Figure 2, E and F). These findings indicate that the diminished osteoclast activity in RXR-KO female mice makes them less prone to bone loss upon OvX. Lack of RXRs leads to formation of giant and nonresorbing osteoclasts in vitro.To determine the mechanism underlying the abnormal osteoclast activation in RXR-KO mice, we cultured bone marrow cells in the presence of the cytokines macrophage colony-stimulating factor (M-CSF) and RANKL (16). Osteoclasts differentiated from RXR-KO bone marrow were significantly larger than WT-derived osteoclasts and contained more nuclei (Figure 3, A-C). In contrast, osteoclast differentiation from bone marrow cells lacking RXRα but not RXRβ was normal, supporting the functional redundancy of RXRα and RXRβ in hematopoietic cells (Supplemental Figure 5). Enlargement of osteoclasts can result in increased bone resorption (17); however, the abnormally large RXR-KO osteoclasts displayed low lytic activity when cultured in calcium-phosphate-coated plates (Figure 3D) or on bovine cortical bone slices ( Figure 3E). RXR-KO osteoclasts also showed low expression of Acp5, matrix metallopeptidase 9 (Mmp9), cathepsin-K (CtsK), and Car2, which encode molecules crucial for extracellular matrix degradation and bone resorption ( Figure 3F). In addition, real-time imaging showed that RXR-KO osteoclasts had an increased spreading over the substrate compared with WT osteoclasts ( Figure 3G and Supplemental Video 1). These in vitro results are consistent with our in vivo observations, indicating that the lack of RXRs in osteoclast progenitors leads to a cell-autonomous effect on osteoclast differentiation and activation.The M-CSF response is altered in RXR-KO osteoclast progenitors. Osteoclast size is determined by the response of osteoclast progenitors to M-CSF, which controls their proliferation and survival (18,19). This cytokine also stimulates activities of the mature resorptive osteoclast, such as spreading, motility, and cytoskeletal organization (20). We thus hypothesized that the RXR-KO osteoclast phenotype could be due to an altered M-CSF response. To test this, we first characterized the capacity of osteoclast progenitors to form myeloid colony-forming units (CFUs) and to divide in response to M-CSF. After 12 days...

Tributyltin Engages Multiple Nuclear Receptor Pathways and Suppresses Osteogenesis in Bone Marrow Multipotent Stromal Cells

“…58 Importantly, RXR recently has been shown to play an essential role in postnatal bone remodeling. 59 It remains to be determined if TBT, bexarotene and LG100268 are recruiting RXR homodimer- or RXR heterodimer-mediated pathways to alter osteogenesis.…”

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Endogenous retinoid X receptor ligands in mouse hematopoietic cells

“…UAS-GFP and Rxra flox/flox × Rxrb flox/flox × Mx1-Cre mice were bred as described (19, 20). RXR deletion was induced by intraperitoneal injecting Rxra flox/flox × Rxrb flox/flox × Mx1-Cre mice with pI:pC 300μg/mouse; 4 doses were given, every other day.…”