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http://dx.doi.org/10.14348/molcells.2019.0232

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

Kim, Kabsun (Department of Pharmacology, Chonnam National University Medical School)
Kim, Jung Ha (Department of Pharmacology, Chonnam National University Medical School)
Kim, Inyoung (Department of Pharmacology, Chonnam National University Medical School)
Seong, Semun (Department of Pharmacology, Chonnam National University Medical School)
Kim, Nacksung (Department of Pharmacology, Chonnam National University Medical School)
Publication Information
Molecules and Cells / v.43, no.1, 2020 , pp. 34-47 More about this Journal
Abstract
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 Rev-erbα 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.
Keywords
bone remodeling; osteoblast; osteoclast; p38 MAPK; Rev-erb;
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1 Ramakrishnan, S.N. and Muscat, G.E. (2006). The orphan Rev-erb nuclear receptors: a link between metabolism, circadian rhythm and inflammation? Nucl. Recept. Signal. 4, e009.
2 Reppert, S.M. and Weaver, D.R. (2002). Coordination of circadian timing in mammals. Nature 418, 935-941.   DOI
3 Rodriguez-Carballo, E., Gamez, B., and Ventura, F. (2016). p38 MAPK signaling in osteoblast differentiation. Front. Cell. Dev. Biol. 4, 40.
4 Roodman, G.D. (2006). Regulation of osteoclast differentiation. Ann. N. Y. Acad. Sci. 1068, 100-109.   DOI
5 Samsa, W.E., Vasanji, A., Midura, R.J., and Kondratov, R.V. (2016). Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype. Bone 84, 194-203.   DOI
6 Schibler, U. and Sassone-Corsi, P. (2002). A web of circadian pacemakers. Cell 111, 919-922.   DOI
7 Schroeder, T.M., Kahler, R.A., Li, X., and Westendorf, J.J. (2004). Histone deacetylase 3 interacts with runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation. J. Biol. Chem. 279, 41998-42007.   DOI
8 Song, C., Tan, P., Zhang, Z., Wu, W., Dong, Y., Zhao, L., Liu, H., Guan, H., and Li, F. (2018). REV-erb agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation. FASEB J. 32, 3215-3228.   DOI
9 Sowa, H., Kaji, H., Yamaguchi, T., Sugimoto, T., and Chihara, K. (2002). Activations of ERK1/2 and JNK by transforming growth factor beta negatively regulate Smad3-induced alkaline phosphatase activity and mineralization in mouse osteoblastic cells. J. Biol. Chem. 277, 36024-36031.   DOI
10 Trump, R.P., Bresciani, S., Cooper, A.W., Tellam, J.P., Wojno, J., Blaikley, J., Orband-Miller, L.A., Kashatus, J.A., Boudjelal, M., Dawson, H.C., et al. (2013). Optimized chemical probes for REV-erbalpha. J. Med. Chem. 56, 4729-4737.   DOI
11 Yin, L. and Lazar, M.A. (2005). The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Mol. Endocrinol. 19, 1452-1459.   DOI
12 Wu, X., Yu, G., Parks, H., Hebert, T., Goh, B.C., Dietrich, M.A., Pelled, G., Izadpanah, R., Gazit, D., Bunnell, B.A., et al. (2008). Circadian mechanisms in murine and human bone marrow mesenchymal stem cells following dexamethasone exposure. Bone 42, 861-870.   DOI
13 Xiao, G., Jiang, D., Gopalakrishnan, R., and Franceschi, R.T. (2002). Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. J. Biol. Chem. 277, 36181-36187.   DOI
14 Xu, C., Ochi, H., Fukuda, T., Sato, S., Sunamura, S., Takarada, T., Hinoi, E., Okawa, A., and Takeda, S. (2016). Circadian clock regulates bone resorption in mice. J. Bone Miner. Res. 31, 1344-1355.   DOI
15 Zamir, I., Zhang, J., and Lazar, M.A. (1997). Stoichiometric and steric principles governing repression by nuclear hormone receptors. Genes Dev. 11, 835-846.   DOI
16 Bohm, C., Hayer, S., Kilian, A., Zaiss, M.M., Finger, S., Hess, A., Engelke, K., Kollias, G., Kronke, G., Zwerina, J., et al. (2009). The alpha-isoform of p38 MAPK specifically regulates arthritic bone loss. J. Immunol. 183, 5938-5947.   DOI
17 Cao, X. and Chen, D. (2005). The BMP signaling and in vivo bone formation. Gene 357, 1-8.   DOI
18 Day, T.F., Guo, X., Garrett-Beal, L., and Yang, Y. (2005). Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739-750.   DOI
19 Duez, H. and Staels, B. (2009). Rev-erb-alpha: an integrator of circadian rhythms and metabolism. J. Appl. Physiol. (1985) 107, 1972-1980.   DOI
20 Fontaine, C., Dubois, G., Duguay, Y., Helledie, T., Vu-Dac, N., Gervois, P., Soncin, F., Mandrup, S., Fruchart, J.C., Fruchart-Najib, J., et al. (2003). The orphan nuclear receptor Rev-erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation. J. Biol. Chem. 278, 37672-37680.   DOI
21 Fujihara, Y., Kondo, H., Noguchi, T., and Togari, A. (2014). Glucocorticoids mediate circadian timing in peripheral osteoclasts resulting in the circadian expression rhythm of osteoclast-related genes. Bone 61, 1-9.   DOI
22 Greenblatt, M.B., Shim, J.H., Zou, W., Sitara, D., Schweitzer, M., Hu, D., Lotinun, S., Sano, Y., Baron, R., Park, J.M., et al. (2010). The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. J. Clin. Invest. 120, 2457-2473.   DOI
23 Harding, H.P. and Lazar, M.A. (1993). The orphan receptor Rev-erbA alpha activates transcription via a novel response element. Mol. Cell. Biol. 13, 3113-3121.   DOI
24 Kim, J., Jang, S., Choi, M., Chung, S., Choe, Y., Choe, H.K., Son, G.H., Rhee, K., and Kim, K. (2018). Abrogation of the circadian nuclear receptor REV-erbalpha exacerbates 6-hydroxydopamine-induced dopaminergic neurodegeneration. Mol. Cells 41, 742-752.   DOI
25 Ziros, P.G., Gil, A.P., Georgakopoulos, T., Habeos, I., Kletsas, D., Basdra, E.K., and Papavassiliou, A.G. (2002). The bone-specific transcriptional regulator Cbfa1 is a target of mechanical signals in osteoblastic cells. J. Biol. Chem. 277, 23934-23941.   DOI
26 Zvonic, S., Ptitsyn, A.A., Kilroy, G., Wu, X., Conrad, S.A., Scott, L.K., Guilak, F., Pelled, G., Gazit, D., and Gimble, J.M. (2007). Circadian oscillation of gene expression in murine calvarial bone. J. Bone Miner. Res. 22, 357-365.   DOI
27 Komori, T. (2011). Signaling networks in RUNX2-dependent bone development. J. Cell. Biochem. 112, 750-755.   DOI
28 He, Y., Lin, F., Chen, Y., Tan, Z., Bai, D., and Zhao, Q. (2015). Overexpression of the circadian clock gene Rev-erbalpha affects murine bone mesenchymal stem cell proliferation and osteogenesis. Stem Cells Dev. 24, 1194-1204.   DOI
29 Iimura, T., Nakane, A., Sugiyama, M., Sato, H., Makino, Y., Watanabe, T., Takagi, Y., Numano, R., and Yamaguchi, A. (2012). A fluorescence spotlight on the clockwork development and metabolism of bone. J. Bone Miner. Metab. 30, 254-269.   DOI
30 Kim, J.H. and Kim, N. (2016). Signaling pathways in osteoclast differentiation. Chonnam Med. J. 52, 12-17.   DOI
31 King, D.P. and Takahashi, J.S. (2000). Molecular genetics of circadian rhythms in mammals. Annu. Rev. Neurosci. 23, 713-742.   DOI
32 Lazar, M.A. (2016). Rev-erbs: integrating metabolism around the clock. In a Time for Metabolism and Hormones, P. Sassone-Corsi and Y. Christen, eds. (Cham, Switzerland: Springer), pp. 63-70.
33 Lazar, M.A., Hodin, R.A., Darling, D.S., and Chin, W.W. (1989). A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat C-erbA alpha transcriptional unit. Mol. Cell. Biol. 9, 1128-1136.   DOI
34 Lee, S.Y., Kim, G.T., Yun, H.M., Kim, Y.C., Kwon, I.K., and Kim, E.C. (2018). Tectorigenin promotes osteoblast differentiation and in vivo bone healing, but suppresses osteoclast differentiation and in vivo bone resorption. Mol. Cells 41, 476-485.   DOI
35 Maury, E., Hong, H.K., and Bass, J. (2014). Circadian disruption in the pathogenesis of metabolic syndrome. Diabetes Metab. 40, 338-346.   DOI
36 Li, X., Liu, N., Gu, B., Hu, W., Li, Y., Guo, B., and Zhang, D. (2018). BMAL1 regulates balance of osteogenic-osteoclastic function of bone marrow mesenchymal stem cells in type 2 diabetes mellitus through the NF-kappaB pathway. Mol. Biol. Rep. 45, 1691-1704.   DOI
37 Liu, A.C., Tran, H.G., Zhang, E.E., Priest, A.A., Welsh, D.K., and Kay, S.A. (2008). Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS Genet. 4, e1000023.   DOI
38 Matsumoto, M., Kogawa, M., Wada, S., Takayanagi, H., Tsujimoto, M., Katayama, S., Hisatake, K., and Nogi, Y. (2004). Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. J. Biol. Chem. 279, 45969-45979.   DOI
39 McDearmon, E.L., Patel, K.N., Ko, C.H., Walisser, J.A., Schook, A.C., Chong, J.L., Wilsbacher, L.D., Song, E.J., Hong, H.K., Bradfield, C.A., et al. (2006). Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice. Science 314, 1304-1308.   DOI
40 McElderry, J.D., Zhao, G., Khmaladze, A., Wilson, C.G., Franceschi, R.T., and Morris, M.D. (2013). Tracking circadian rhythms of bone mineral deposition in murine calvarial organ cultures. J. Bone Miner. Res. 28, 1846-1854.   DOI
41 Ogawa, S., Lozach, J., Jepsen, K., Sawka-Verhelle, D., Perissi, V., Sasik, R., Rose, D.W., Johnson, R.S., Rosenfeld, M.G., and Glass, C.K. (2004). A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation. Proc. Natl. Acad. Sci. U. S. A. 101, 14461-14466.   DOI