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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

Morusin Inhibits RANKL-induced Osteoclastogenesis and Ovariectomized Osteoporosis

Author(s): Cong Jin, Jiewen Zheng, Qichang Yang, Yewei Jia, Haibo Li, Xuewen Liu, Yangjun Xu, Zhuolin Chen and Lei He*

Volume 27, Issue 9, 2024

Published on: 02 October, 2023

Page: [1358 - 1370] Pages: 13

DOI: 10.2174/0113862073252310230925062415

Price: $65

Abstract

Background: Postmenopausal osteoporosis (PMOP) is a classic type of osteoporosis that has gradually become a significant health problem worldwide. There is an urgent need for a safe alternative therapeutic agent considering the poor therapeutic strategies currently available for this disease. The roots and bark of the Morus australis tree (Moraceae) are used to make a traditional Chinese medicine known as "Morusin", and accumulating evidence has demonstrated its multiple activities, such as anti-inflammatory and anti-tumor effects.

Objective: In this study, we aim to explore the effect of Morusin on mouse osteoclasts and its mechanism.

Methods: In this study, we explored the inhibitory effects of Morusin on murine osteoclasts in vitro and its mechanism, and the protective effect of Morusin on an ovariectomy (OVX)-induced osteoporosis model in vivo.

Results: The results showed that Morusin prevented OVX-induced bone loss and dramatically decreased RANKL-induced osteoclastogenesis. Morusin interfered with RANKL-activated NF- κB, MAPK, and PI3K/AKT signaling pathways. The expression of three master factors that control osteoclast differentiation, c-Fos, NFATc1, and c-Jun, was reduced by Morusin treatment. Collectively, in vitro results indicated that Morusin has a protective effect on OVX-induced bone loss in a mouse model.

Conclusion: Our data provide encouraging evidence that Morusin may be an effective treatment for PMOP.

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[1]
Seeman, E. Reduced bone formation and increased bone resorption: Rational targets for the treatment of osteoporosis. Osteoporos. Int., 2003, 14(S3), 2-8.
[http://dx.doi.org/10.1007/s00198-002-1340-9] [PMID: 12730770]
[2]
Black, D.M.; Rosen, C.J. Postmenopausal osteoporosis. N. Engl. J. Med., 2016, 374(3), 254-262.
[http://dx.doi.org/10.1056/NEJMcp1513724] [PMID: 26789873]
[3]
Eastell, R.; O’Neill, T.W.; Hofbauer, L.C.; Langdahl, B.; Reid, I.R.; Gold, D.T.; Cummings, S.R. Postmenopausal osteoporosis. Nat. Rev. Dis. Primers, 2016, 2(1), 16069.
[http://dx.doi.org/10.1038/nrdp.2016.69] [PMID: 27681935]
[4]
Aki, S.; Eskiyurt, N.; Akarırmak, Ü.; Tüzün, F.; Eryavuz, M.; Alper, S.; Arpacıoğlu, O.; Atalay, F.; Kavuncu, V.; Kokino, S.; Kuru, Ö.; Nas, K.; Özerbil, Ö.; Savaş, G.; Sendur, Ö.F.; Soy, D.; Akyüz, G. Gastrointestinal side effect profile due to the use of alendronate in the treatment of osteoporosis. Yonsei Med. J., 2003, 44(6), 961-967.
[http://dx.doi.org/10.3349/ymj.2003.44.6.961] [PMID: 14703602]
[5]
Boyle, W.J.; Simonet, W.S.; Lacey, D.L. Osteoclast differentiation and activation. Nature, 2003, 423(6937), 337-342.
[http://dx.doi.org/10.1038/nature01658] [PMID: 12748652]
[6]
Teitelbaum, S.L. Bone resorption by osteoclasts. Science., 2000, 289(5484), 1504-1508.
[http://dx.doi.org/10.1126/science.289.5484.1504] [PMID: 10968780]
[7]
Wada, T.; Nakashima, T.; Hiroshi, N.; Penninger, J.M. RANKL–RANK signaling in osteoclastogenesis and bone disease. Trends Mol. Med., 2006, 12(1), 17-25.
[http://dx.doi.org/10.1016/j.molmed.2005.11.007] [PMID: 16356770]
[8]
Nakagawa, N.; Kinosaki, M.; Yamaguchi, K.; Shima, N.; Yasuda, H.; Yano, K.; Morinaga, T.; Higashio, K. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem. Biophys. Res. Commun., 1998, 253(2), 395-400.
[http://dx.doi.org/10.1006/bbrc.1998.9788] [PMID: 9878548]
[9]
Lamothe, B.; Webster, W.K.; Gopinathan, A.; Besse, A.; Campos, A.D.; Darnay, B.G. TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation. Biochem. Biophys. Res. Commun., 2007, 359(4), 1044-1049.
[http://dx.doi.org/10.1016/j.bbrc.2007.06.017] [PMID: 17572386]
[10]
Sanz, L.; Diaz-Meco, M.T.; Nakano, H.; Moscat, J. The atypical PKC-interacting protein p62 channels NF-kappa B activation by the IL-1-TRAF6 pathway. EMBO J., 2000, 19(7), 1576-1586.
[http://dx.doi.org/10.1093/emboj/19.7.1576] [PMID: 10747026]
[11]
Walsh, M.C.; Kim, G.K.; Maurizio, P.L.; Molnar, E.E.; Choi, Y. TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL. PLoS One, 2008, 3(12), e4064.
[http://dx.doi.org/10.1371/journal.pone.0004064] [PMID: 19112497]
[12]
Kim, J.H.; Kim, N. Signaling pathways in osteoclast differentiation. Chonnam Med. J., 2016, 52(1), 12-17.
[http://dx.doi.org/10.4068/cmj.2016.52.1.12] [PMID: 26865996]
[13]
Kim, J.H.; Kim, N. Regulation of NFATc1 in osteoclast differentiation. J. Bone Metab., 2014, 21(4), 233-241.
[http://dx.doi.org/10.11005/jbm.2014.21.4.233] [PMID: 25489571]
[14]
Zhao, Q.; Wang, X.; Liu, Y.; He, A.; Jia, R. NFATc1: Functions in osteoclasts. Int. J. Biochem. Cell Biol., 2010, 42(5), 576-579.
[http://dx.doi.org/10.1016/j.biocel.2009.12.018] [PMID: 20035895]
[15]
Wang, F.; Zhang, D.; Mao, J.; Ke, X.X.; Zhang, R.; Yin, C.; Gao, N.; Cui, H. Morusin inhibits cell proliferation and tumor growth by down-regulating c-Myc in human gastric cancer. Oncotarget, 2017, 8(34), 57187-57200.
[http://dx.doi.org/10.18632/oncotarget.19231] [PMID: 28915664]
[16]
Wang, L.; Guo, H.; Yang, L.; Dong, L.; Lin, C.; Zhang, J.; Lin, P.; Wang, X. Morusin inhibits human cervical cancer stem cell growth and migration through attenuation of NF-κB activity and apoptosis induction. Mol. Cell. Biochem., 2013, 379(1-2), 7-18.
[http://dx.doi.org/10.1007/s11010-013-1621-y] [PMID: 23543150]
[17]
Vochyánová, Z.; Pokorná, M.; Rotrekl, D.; Smékal, V.; Fictum, P.; Suchý, P.; Gajdziok, J.; Šmejkal, K.; Hošek, J. Prenylated flavonoid morusin protects against TNBS-induced colitis in rats. PLoS One, 2017, 12(8), e0182464.
[http://dx.doi.org/10.1371/journal.pone.0182464] [PMID: 28797051]
[18]
Matsuo, K.; Owens, J.M.; Tonko, M.; Elliott, C.; Chambers, T.J.; Wagner, E.F. Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nat. Genet., 2000, 24(2), 184-187.
[http://dx.doi.org/10.1038/72855] [PMID: 10655067]
[19]
Yagi, M.; Miyamoto, T.; Sawatani, Y.; Iwamoto, K.; Hosogane, N.; Fujita, N.; Morita, K.; Ninomiya, K.; Suzuki, T.; Miyamoto, K.; Oike, Y.; Takeya, M.; Toyama, Y.; Suda, T. DC-STAMP is essential for cell–cell fusion in osteoclasts and foreign body giant cells. J. Exp. Med., 2005, 202(3), 345-351.
[http://dx.doi.org/10.1084/jem.20050645] [PMID: 16061724]
[20]
Kim, K.; Lee, S.H.; Ha Kim, J.; Choi, Y.; Kim, N. NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol. Endocrinol., 2008, 22(1), 176-185.
[http://dx.doi.org/10.1210/me.2007-0237] [PMID: 17885208]
[21]
Ljusberg, J.; Wang, Y.; Lång, P.; Norgård, M.; Dodds, R.; Hultenby, K.; Ek-Rylander, B.; Andersson, G. Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts. J. Biol. Chem., 2005, 280(31), 28370-28381.
[http://dx.doi.org/10.1074/jbc.M502469200] [PMID: 15929988]
[22]
Lee, K.; Chung, Y.H.; Ahn, H.; Kim, H.; Rho, J.; Jeong, D. Selective regulation of MAPK signaling mediates RANKL-dependent osteoclast differentiation. Int. J. Biol. Sci., 2016, 12(2), 235-245.
[http://dx.doi.org/10.7150/ijbs.13814] [PMID: 26884720]
[23]
Moon, J.B.; Kim, J.H.; Kim, K.; Youn, B.U.; Ko, A.; Lee, S.Y.; Kim, N. Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade. J. Immunol., 2012, 188(1), 163-169.
[http://dx.doi.org/10.4049/jimmunol.1101254] [PMID: 22131333]
[24]
Kim, H.K.; Nelson-Dooley, C.; Della-Fera, M.A.; Yang, J.Y.; Zhang, W.; Duan, J.; Hartzell, D.L.; Hamrick, M.W.; Baile, C.A. Genistein decreases food intake, body weight, and fat pad weight and causes adipose tissue apoptosis in ovariectomized female mice. J. Nutr., 2006, 136(2), 409-414.
[http://dx.doi.org/10.1093/jn/136.2.409] [PMID: 16424120]
[25]
Werner, H.J.; Martin, H.; Behrend, D.; Schmitz, K.P.; Schober, H.C. The loss of stiffness as osteoporosis progresses. Med. Eng. Phys., 1996, 18(7), 601-606.
[http://dx.doi.org/10.1016/1350-4533(96)00012-4] [PMID: 8892246]
[26]
Riggs, B.L.; Melton, L.J., III Involutional Osteoporosis. N. Engl. J. Med., 1986, 314(26), 1676-1686.
[http://dx.doi.org/10.1056/NEJM198606263142605] [PMID: 3520321]
[27]
Rachner, T.D.; Khosla, S.; Hofbauer, L.C. Osteoporosis: Now and the future. Lancet, 2011, 377(9773), 1276-1287.
[http://dx.doi.org/10.1016/S0140-6736(10)62349-5] [PMID: 21450337]
[28]
Khan, M.; Cheung, A.M.; Khan, A.A. Drug-related adverse events of osteoporosis therapy. Endocrinol. Metab. Clin. North Am., 2017, 46(1), 181-192.
[http://dx.doi.org/10.1016/j.ecl.2016.09.009] [PMID: 28131131]
[29]
Jia, Y.; Jiang, J.; Lu, X.; Zhang, T.; Zhao, K.; Han, W.; Yang, W.; Qian, Y. Garcinol suppresses RANKL‐induced osteoclastogenesis and its underlying mechanism. J. Cell. Physiol., 2019, 234(5), 7498-7509.
[http://dx.doi.org/10.1002/jcp.27511] [PMID: 30471112]
[30]
Zhao, K.; Jia, Y.; Peng, J.; Pang, C.; Zhang, T.; Han, W.; Jiang, J.; Lu, X.; Zhu, J.; Qian, Y. Anacardic acid inhibits RANKL‐induced osteoclastogenesis in vitro and prevents ovariectomy‐induced bone loss in vivo. FASEB J., 2019, 33(8), 9100-9115.
[http://dx.doi.org/10.1096/fj.201802575RR] [PMID: 31050917]
[31]
Li, H.; Wang, Q.; Dong, L.; Liu, C.; Sun, Z.; Gao, L.; Wang, X. Morusin suppresses breast cancer cell growth in vitro and in vivo through C/EBPβ and PPARγ mediated lipoapoptosis. J. Exp. Clin. Cancer Res., 2015, 34(1), 137.
[http://dx.doi.org/10.1186/s13046-015-0252-4] [PMID: 26538209]
[32]
Jia, Y.; He, W.; Zhang, H.; He, L.; Wang, Y.; Zhang, T.; Peng, J.; Sun, P.; Qian, Y. Morusin ameliorates IL-1β-induced chondrocyte inflammation and osteoarthritis via NF-κB signal pathway. Drug Des. Devel. Ther., 2020, 14, 1227-1240.
[http://dx.doi.org/10.2147/DDDT.S244462] [PMID: 32273685]
[33]
Chen, M.; Han, H.; Zhou, S.; Wen, Y.; Chen, L. Morusin induces osteogenic differentiation of bone marrow mesenchymal stem cells by canonical Wnt/β-catenin pathway and prevents bone loss in an ovariectomized rat model. Stem Cell Res. Ther., 2021, 12(1), 173.
[http://dx.doi.org/10.1186/s13287-021-02239-3] [PMID: 33712069]
[34]
Lin, B.; Huang, J.F.; Liu, X.W.; Ma, X.T.; Liu, X.L.; Lu, Y.; Zhou, Y.; Guo, F.M.; Feng, T.T. Rapid, microwave-accelerated synthesis and anti-osteoporosis activities evaluation of Morusin scaffolds and Morusignin L scaffolds. Bioorg. Med. Chem. Lett., 2017, 27(11), 2389-2396.
[http://dx.doi.org/10.1016/j.bmcl.2017.04.018] [PMID: 28427808]
[35]
Genant, H.K.; Baylink, D.J.; Gallagher, J.C. Estrogens in the prevention of osteoporosis in postmenopausal women. Am. J. Obstet. Gynecol., 1989, 161(6), 1842-1846.
[http://dx.doi.org/10.1016/S0002-9378(89)80004-3] [PMID: 2690636]
[36]
Takayanagi, H.; Kim, S.; Koga, T.; Nishina, H.; Isshiki, M.; Yoshida, H.; Saiura, A.; Isobe, M.; Yokochi, T.; Inoue, J.; Wagner, E.F.; Mak, T.W.; Kodama, T.; Taniguchi, T. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell, 2002, 3(6), 889-901.
[http://dx.doi.org/10.1016/S1534-5807(02)00369-6] [PMID: 12479813]
[37]
Soysa, N.S.; Alles, N. NF-κB functions in osteoclasts. Biochem. Biophys. Res. Commun., 2009, 378(1), 1-5.
[http://dx.doi.org/10.1016/j.bbrc.2008.10.146] [PMID: 18992710]
[38]
Ross, F.P. M-CSF, c-Fms, and signaling in osteoclasts and their precursors. Ann. N. Y. Acad. Sci., 2006, 1068(1), 110-116.
[http://dx.doi.org/10.1196/annals.1346.014] [PMID: 16831911]
[39]
Li, X.; Udagawa, N.; Itoh, K.; Suda, K.; Murase, Y.; Nishihara, T.; Suda, T.; Takahashi, N. p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function. Endocrinology., 2002, 143(8), 3105-3113.
[http://dx.doi.org/10.1210/endo.143.8.8954] [PMID: 12130576]
[40]
Lee, M.S.; Kim, H.S.; Yeon, J.T.; Choi, S.W.; Chun, C.H.; Kwak, H.B.; Oh, J. GM-CSF regulates fusion of mononuclear osteoclasts into bone-resorbing osteoclasts by activating the Ras/ERK pathway. J. Immunol., 2009, 183(5), 3390-3399.
[http://dx.doi.org/10.4049/jimmunol.0804314] [PMID: 19641137]
[41]
Yamanaka, Y.; Clohisy, J.C.F.; Ito, H.; Matsuno, T.; Abu-Amer, Y. Blockade of JNK and NFAT pathways attenuates orthopedic particle-stimulated osteoclastogenesis of human osteoclast precursors and murine calvarial osteolysis. J. Orthop. Res., 2013, 31(1), 67-72.
[http://dx.doi.org/10.1002/jor.22200] [PMID: 22847537]
[42]
Wagner, E.F. Bone development and inflammatory disease is regulated by AP-1 (Fos/Jun). Ann. Rheum. Dis., 2010, 69(S1), i86-i88.
[http://dx.doi.org/10.1136/ard.2009.119396] [PMID: 19995753]
[43]
Bonetti, B.; Stegagno, C.; Cannella, B.; Rizzuto, N.; Moretto, G.; Raine, C.S. Activation of NF-kappaB and c-jun transcription factors in multiple sclerosis lesions. Implications for oligodendrocyte pathology. Am. J. Pathol., 1999, 155(5), 1433-1438.
[http://dx.doi.org/10.1016/S0002-9440(10)65456-9] [PMID: 10550297]
[44]
Chiu, Y.C.; Lin, C.Y.; Chen, C.P.; Huang, K.C.; Tong, K.M.; Tzeng, C.Y.; Lee, T.S.; Hsu, H.C.; Tang, C.H. Peptidoglycan enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, focal adhesion kinase, Akt, and AP-1- dependent pathway. J. Immunol., 2009, 183(4), 2785-2792.
[http://dx.doi.org/10.4049/jimmunol.0802826] [PMID: 19635908]
[45]
Kalu, D.N. The ovariectomized rat model of postmenopausal bone loss. Bone Miner., 1991, 15(3), 175-191.
[http://dx.doi.org/10.1016/0169-6009(91)90124-I] [PMID: 1773131]

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