Hymenialdisine: A Marine Natural Product That Acts on Both Osteoblasts and Osteoclasts and Prevents Estrogen-Dependent Bone Loss in Mice.
HYMENIALDISINE
MARINE NATURAL COMPOUND
OSTEOBLASTS
OSTEOCLASTS
RANKL
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
01
11
2019
revised:
31
03
2020
accepted:
02
04
2020
pubmed:
15
4
2020
medline:
29
7
2021
entrez:
15
4
2020
Statut:
ppublish
Résumé
Excessive osteoclast (OC) activity together with relatively weak osteoblast (OB) function are strongly connected to osteolytic diseases, including osteoporosis, tumor-induced osteolysis, and inflammatory bone erosion. Very few natural products or compounds have been shown to exert therapeutic effects on both OCs and OBs, limiting the potential development of natural compounds for clinical application. Hymenialdisine (HMD) is a marine sponge-derived natural inhibitor of protein kinases with previously reported anti-osteoarthritis and anti-cancer properties. However, the roles of HMD in OCs, OBs, and osteoporosis have not yet been well established. Here, we found that HMD not only suppressed osteoclastogenesis but also promoted OB differentiation. HMD exerted dose-dependent inhibitory effects on RANKL-induced OC formation, bone resorption, and OC-specific gene expression. These strong inhibitory effects were achieved by blocking the NF-κB and MAPK signaling pathways, and NFATc1 expression. In addition, HMD potentially stimulated OB differentiation by activating alkaline phosphatase (ALP) and enhancing OB matrix mineralization. We found that HMD can activate the glycogen synthase kinase 3β (GSK-3β)/β-catenin/T-cell factor (TCF)/lymphoid enhancer factor (LEF) signaling pathway to upregulate Runx-2 expression, the main transcription factor in this pathway. Increased expression of Runx-2 was also correlated with expression of the OB-specific genes Col1a1 and osteocalcin (Ocn). Furthermore, we also evaluated the therapeutic potential of HMD in a female C57BL/6j mouse model of ovariectomy (OVX)-induced systematic bone loss. HMD showed a remarkable ability to prevent decreases in bone volume (BV/TV) and trabecular thickness (Tb.Th). In summary, HMD exerts notable effects in inhibiting OC-related osteolysis and enhancing OB-induced ossification, suggesting the potential application of HMD in osteoporosis treatment. © 2020 American Society for Bone and Mineral Research.
Substances chimiques
Azepines
0
Biological Products
0
Estrogens
0
NF-kappa B
0
NFATC Transcription Factors
0
Pyrroles
0
RANK Ligand
0
hymenialdisine
95569-43-0
Glycogen Synthase Kinase 3
EC 2.7.11.26
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1582-1596Informations de copyright
© 2020 American Society for Bone and Mineral Research.
Références
Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359-81.
Malve H. Exploring the ocean for new drug developments: Marine pharmacology. J Pharm Bioallied Sci. 2016;8(2):83-91.
Mayer AMS, Rodriguez AD, Taglialatela-Scafati O, Fusetani N. Marine pharmacology in 2012-2013: marine compounds with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action. Mar Drugs. 2017;15(9):273.
Jimenez C. Marine natural products in medicinal chemistry. ACS Med Chem Lett. 2018;9(10):959-61.
Zulfiqar B, Jones AJ, Sykes ML, Shelper TB, Davis RA, Avery VM. Screening a natural product-based library against kinetoplastid parasites. Molecules. 2017;22(10):1715.
Nguyen TN, Tepe JJ. Preparation of hymenialdisine, analogues and their evaluation as kinase inhibitors. Curr Med Chem. 2009;16(24):3122-43.
Wan Y, Hur W, Cho CY, et al. Synthesis and target identification of hymenialdisine analogs. Chem Biol. 2004;11(2):247-59.
D'Orazio N, Gammone MA, Gemello E, De Girolamo M, Cusenza S, Riccioni G. Marine bioactives: pharmacological properties and potential applications against inflammatory diseases. Mar Drugs. 2012;10(4):812-33.
Chen K, Qiu P, Yuan Y, et al. Pseurotin a inhibits osteoclastogenesis and prevents ovariectomized-induced bone loss by suppressing reactive oxygen species. Theranostics. 2019;9(6):1634-50.
van Noort M, Clevers H. TCF transcription factors, mediators of Wnt-signaling in development and cancer. Dev Biol. 2002;244(1):1-8.
Wang C, Steer JH, Joyce DA, Yip KH, Zheng MH, Xu J. 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits osteoclastogenesis by suppressing RANKL-induced NF-kappaB activation. J Bone Miner Res. 2003;18(12):2159-68.
van der Kraan AG, Chai RC, Singh PP, et al. HSP90 inhibitors enhance differentiation and MITF (microphthalmia transcription factor) activity in osteoclast progenitors. Biochem J. 2013;451(2):235-44.
Wedemeyer C, Xu J, Neuerburg C, et al. Particle-induced osteolysis in three-dimensional micro-computed tomography. Calcif Tissue Int. 2007;81(5):394-402.
Zhai ZJ, Li HW, Liu GW, et al. Andrographolide suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo. Br J Pharmacol. 2014;171(3):663-75.
Sousa DM, Conceição F, Silva DI, et al. Ablation of Y1 receptor impairs osteoclast bone-resorbing activity. Sci Rep. 2016;6:33470.
Kim JH, Kim N. Signaling pathways in osteoclast differentiation. Chonnam Med J. 2016;52(1):12-7.
Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337-42.
Brown KD, Claudio E, Siebenlist U. The roles of the classical and alternative nuclear factor-kappaB pathways: potential implications for autoimmunity and rheumatoid arthritis. Arthritis Res Ther. 2008;10(4):212.
Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone. 2007;40(2):251-64.
Crotti TN, Sharma SM, Fleming JD, et al. PU.1 and NFATc1 mediate osteoclastic induction of the mouse beta3 integrin promoter. J Cell Physiol. 2008;215(3):636-44.
Matsuo K, Galson DL, Zhao C, et al. Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem. 2004;279(25):26475-80.
Takayanagi H, Kim S, Koga T, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3(6):889-901.
Liu Y, Shepherd EG, Nelin LD. MAPK phosphatases-regulating the immune response. Nat Rev Immunol. 2007;7(3):202-12.
Ikeda F, Nishimura R, Matsubara T, et al. Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest. 2004;114(4):475-84.
Miyazaki T, Katagiri H, Kanegae Y, et al. Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts. J Cell Biol. 2000;148(2):333-42.
Negishi-Koga T, Takayanagi H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev. 2009;231(1):241-56.
Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377(15):1417-27.
Liu SP, Wang GD, Du XJ, et al. Triptolide inhibits the function of TNF-alpha in osteoblast differentiation by inhibiting the NF-kappaB signaling pathway. Exp Ther Med. 2017;14(3):2235-40.
Komori T. Signaling networks in RUNX2-dependent bone development. J Cell Biochem. 2011;112(3):750-5.
Wu D, Pan W. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci. 2010;35(3):161-8.
Weske S, Vaidya M, Reese A, et al. Targeting sphingosine-1-phosphate lyase as an anabolic therapy for bone loss. Nat Med. 2018;24(5):667-78.
Sharpe C, Lawrence N, Martinez AA. Wnt signalling: a theme with nuclear variations. Bioessays. 2001;23(4):311-8.
Zhang M, Yan Y, Lim YB, et al. BMP-2 modulates beta-catenin signaling through stimulation of Lrp5 expression and inhibition of beta-TrCP expression in osteoblasts. J Cell Biochem. 2009;108(4):896-905.
Zhang N, Zhong R, Yan H, Jiang Y. Structural features underlying selective inhibition of GSK3beta by dibromocantharelline: implications for rational drug design. Chem Biol Drug Des. 2011;77(3):199-205.
Meijer L, Thunnissen AM, White AW, et al. Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent. Chem Biol. 2000;7(1):51-63.
Moon JB, Kim JH, Kim K, et al. Akt induces osteoclast differentiation through regulating the GSK3beta/NFATc1 signaling cascade. J Immunol. 2012;188(1):163-9.
Fan X, Xiong H, Wei J, et al. Cytoplasmic hnRNPK interacts with GSK3beta and is essential for the osteoclast differentiation. Sci Rep. 2015;5:17732.
Wu M, Chen W, Lu Y, Zhu G, Hao L, Li Y-P. Gα13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3β-NFATc1 signalling pathway. Nat Commun. 2017;8:13700.
Luo J, Yang Z, Ma Y, et al. LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat Med. 2016;22(5):539-46.
Suzuki N, Somei M, Kitamura K, Reiter RJ, Hattori A. Novel bromomelatonin derivatives suppress osteoclastic activity and increase osteoblastic activity: implications for the treatment of bone diseases. J Pineal Res. 2008;44(3):326-34.