Rev-erbα Negatively Regulates Osteoclast and Osteoblast Differentiation through p38 MAPK Signaling Pathway.

Jan 4, 2020Molecules and cells

Rev-erbα reduces bone cell development by affecting the p38 MAPK signaling pathway

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Abstract

Rev-erbα negatively regulates differentiation of osteoclasts and osteoblasts.

Knockdown of Rev-erbα in osteoclast precursor cells increased RANKL-induced osteoclast formation and expression of key osteoclast markers.
Overexpression of Rev-erbα decreased NFATc1 expression by inhibiting c-Fos recruitment to its promoter.
In osteoblast precursors, Rev-erbα overexpression reduced expression of osteoblast marker genes, including Runx2 and alkaline phosphatase.
Rev-erbα interfered with Runx2 recruitment to the promoter of target genes related to osteoblast differentiation.
Knockdown of Rev-erbα in osteoblast precursors enhanced their differentiation and function.
Rev-erbα also negatively regulated differentiation of both osteoclasts and osteoblasts by suppressing the p38 MAPK pathway.

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The circadian clock regulates various physiological processes, including bone metabolism. The nuclear receptors Reverbs, comprising Rev-erbα and Rev-erbβ, play a key role as transcriptional regulators of the circadian clock. In this study, we demonstrate that Rev-erbs negatively regulate differentiation of osteoclasts and osteoblasts. The knockdown of Rev-erbα in osteoclast precursor cells enhanced receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation, as well as expression of nuclear factor of activated T cells 1 (NFATc1), osteoclast-associated receptor (OSCAR), and tartrate-resistant acid phosphatase (TRAP). The overexpression of Rev-erbα leads to attenuation of the NFATc1 expression via inhibition of recruitment of c-Fos to the NFATc1 promoter. The overexpression of Rev-erbα in osteoblast precursors attenuated the expression of osteoblast marker genes including Runx2, alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OC). Rev-erbα interfered with the recruitment of Runx2 to the promoter region of the target genes. Conversely, knockdown of Reverbα in the osteoblast precursors enhanced the osteoblast differentiation and function. In addition, Rev-erbα negatively regulated osteoclast and osteoblast differentiation by suppressing the p38 MAPK pathway. Furthermore, intraperitoneal administration of GSK4112, a Rev-erb agonist, protects RANKL-induced bone loss via inhibition of osteoclast differentiation in vivo . Taken together, our results demonstrate a molecular mechanism of Rev-erbs in the bone remodeling, and provide a molecular basis for a potential therapeutic target for treatment of bone disease characterized by excessive bone resorption.

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Rev-erbα Negatively Regulates Osteoclast and Osteoblast Differentiation through p38 MAPK Signaling Pathway.

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