REV‐ERB agonism suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss partially via FABP4 upregulation

Feb 7, 2018FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Activating REV-ERB reduces bone-destroying cells and helps prevent bone loss after ovary removal partly by increasing FABP4

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Abstract

REV-ERBα levels decreased significantly during RANKL-induced osteoclast differentiation from primary bone marrow-derived macrophages.

Knocking down REV-ERBα in macrophages enhanced the formation of osteoclasts.
REV-ERBβ knockdown did not affect osteoclast differentiation.
The REV-ERB agonist SR9009 inhibited both osteoclast differentiation and bone resorption.
Administering SR9009 prevented ovariectomy-induced bone loss and was linked to decreased serum RANKL and C-terminal telopeptide levels.
SR9009 suppressed the activation of certain signaling pathways and reduced levels of reactive oxygen species.
FABP4, an intracellular lipid-binding protein, was up-regulated by REV-ERB agonism, which partially contributed to the inhibition of osteoclastogenesis.

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REV-ERBs (REV-ERBα and REV-ERBβ) are transcription repressors and circadian regulators. Previous investigations have shown that REV-ERBs repress the expression of target genes, including MMP9 and CX3CR1, in macrophages. Because MMP9 and CX3CR1 reportedly participate in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, we inferred that REV-ERBs might play a role in osteoclastogenesis. In the present study, we found that the REV-ERBα level decreased significantly during RANKL-induced osteoclast differentiation from primary bone marrow-derived macrophages (BMMs). REV-ERBα knockdown by small interfering RNA in BMMs resulted in the enhanced formation of osteoclasts, whereas REV-ERBβ knockdown showed no effect on osteoclast differentiation. Moreover, the REV-ERB agonist SR9009 inhibited osteoclast differentiation and bone resorption. Intraperitoneal SR9009 administration prevented ovariectomy-induced bone loss; this effect was accompanied by decreased serum RANKL and C-terminal telopeptide of type I collagen levels and increased osteoprotegerin levels. Further investigation revealed that NF-κB and MAPK activation and nuclear factor of activated T cells, cytoplasmic 1, and c-fos expression were suppressed by SR9009. The level of reactive oxygen species was also decreased by SR9009, with NADPH oxidase subunits also being down-regulated. In addition, an expression microarray showed that FABP4, an intracellular lipid-binding protein, was up-regulated by REV-ERB agonism. BMS309403, an inhibitor of FABP4, partially prevented the suppression of osteoclastogenesis by SR9009 through stabilizing phosphorylation of p65. To summarize, our results proved that the REV-ERB agonism inhibited osteoclastogenesis partially via FABP4 up-regulation.-Song, C., Tan, P., Zhang, Z., Wu, W., Dong, Y., Zhao, L., Liu, H., Guan, H., Li, F. REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation.

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REV‐ERB agonism suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss partially via FABP4 upregulation

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