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http://dx.doi.org/10.5483/BMBRep.2020.53.3.147

Physalin D inhibits RANKL-induced osteoclastogenesis and bone loss via regulating calcium signaling  

Ding, Ning (Department of Blood Purification, General Hospital of Shenyang Military Area Command)
Lu, Yanzhu (Department of Orthopedics, Southwest Hospital, Third Military Medical University (Army Medical University))
Cui, Hanmin (Department of Blood Purification, General Hospital of Shenyang Military Area Command)
Ma, Qinyu (Department of Orthopedics, Southwest Hospital, Third Military Medical University (Army Medical University))
Qiu, Dongxia (Department of Blood Purification, General Hospital of Shenyang Military Area Command)
Wei, Xueting (Department of Blood Purification, General Hospital of Shenyang Military Area Command)
Dou, Ce (Department of Orthopedics, Southwest Hospital, Third Military Medical University (Army Medical University))
Cao, Ning (Department of Blood Purification, General Hospital of Shenyang Military Area Command)
Publication Information
BMB Reports / v.53, no.3, 2020 , pp. 154-159 More about this Journal
Abstract
We investigated the effects of physalin A, B, D, and F on osteoclastogenesis induced by receptor activator of nuclear factor κB ligand (RANKL). The biological functions of different physalins were first predicted using an in silico bioinformatic tool (BATMAN-TCM). Afterwards, we tested cell viability and cell apoptosis rate to analyze the cytotoxicity of different physalins. We analyzed the inhibitory effects of physalins on RANKL-induced osteoclastogenesis from mouse bone-marrow macrophages (BMMs) using a tartrate-resistant acid phosphatase (TRAP) stain. We found that physalin D has the best selectivity index (SI) among all analyzed physalins. We then confirmed the inhibitory effects of physalin D on osteoclast maturation and function by immunostaining of F-actin and a pit-formation assay. On the molecular level, physalin D attenuated RANKL-evoked intracellular calcium ([Ca(2+)](i)) oscillation by inhibiting phosphorylation of phospholipase Cγ2 (PLCγ2) and thus blocked the downstream activation of Ca2+/calmodulin-dependent protein kinases (CaMK)IV and cAMP-responsive element-binding protein (CREB). An animal study showed that physalin D treatment rescues bone microarchitecture, prevents bone loss, and restores bone strength in a model of rapid bone loss induced by soluble RANKL. Taken together, these results suggest that physalin D inhibits RANKL-induced osteoclastogenesis and bone loss via suppressing the PLCγ2-CaMK-CREB pathway.
Keywords
Bone; Calcium Signaling; Osteoclast; Osteoporosis; Physalin;
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1 Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nature reviews. Immunology 7, 292-304
2 Wada T, Nakashima T, Hiroshi N and Penninger JM (2006) RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 12, 17-25   DOI
3 Liu H, Wang K, Xia G et al (2018) Two sulfonate metabolites of physalin A in rats. Xenobiotica 48, 11-17   DOI
4 Hsu CC, Wu YC, Farh L et al (2012) Physalin B from Physalis angulata triggers the NOXA-related apoptosis pathway of human melanoma A375 cells. Food Chem Toxicol 50, 619-624   DOI
5 Vandenberghe I, Creancier L, Vispe S et al (2008) Physalin B, a novel inhibitor of the ubiquitin-proteasome pathway, triggers NOXA-associated apoptosis. Biochem Pharmacol 76, 453-462   DOI
6 Chamoux E, Bisson M, Payet MD and Roux S (2010) TRPV-5 mediates a receptor activator of NF-kappaB (RANK) ligandinduced increase in cytosolic Ca2+ in human osteoclasts and down-regulates bone resorption. J Biol Chem 285, 25354-25362   DOI
7 Sato K, Suematsu A, Nakashima T et al (2006) Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med 12, 1410-1416   DOI
8 Kajiya H (2012) Calcium signaling in osteoclast differentiation and bone resorption. Adv Exp Med Biol 740, 917-932   DOI
9 Dou C, Zhang C, Kang F et al (2014) MiR-7b directly targets DC-STAMP causing suppression of NFATc1 and c-Fos signaling during osteoclast fusion and differentiation. Biochim Biophys Acta 1839, 1084-1096   DOI
10 Tomimori Y, Mori K, Koide M et al (2009) Evaluation of pharmaceuticals with a novel 50-hour animal model of bone loss. J Bones Miner Res 24, 1194-1205   DOI
11 Zheng Y, Chen J, Liu L, Liang X and Hong D (2016) In vivo pharmacokinetics of and tissue distribution study of physalin B after intravenous administration in rats by liquid chromatography with tandem mass spectrometry. Biomed Chromatogr 30, 1278-1284   DOI
12 Dou C, Ding N, Xing J et al (2016) Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway. Cell Death Dis 7, e2162   DOI
13 Li P, Liu C, Hu M, Long M, Zhang D and Huo B (2014) Fluid flow-induced calcium response in osteoclasts: signaling pathways. Ann Biomed Eng 42, 1250-1260   DOI
14 Hadjidakis DJ and Androulakis II (2006) Bone remodeling. Ann New York Acad Sci 1092, 385-396   DOI
15 Rodan GA and Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289, 1508-1514   DOI
16 Bastos GN, Silveira AJ, Salgado CG, Picanco-Diniz DL and do Nascimento JL (2008) Physalis angulata extract exerts anti-inflammatory effects in rats by inhibiting different pathways. J Ethnopharmacol 118, 246-251   DOI
17 Yasuda H, Shima N, Nakagawa N et al (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Nat Acad Sci U S A 95, 3597-3602   DOI
18 Hwang SY and Putney JW Jr (2011) Calcium signaling in osteoclasts. Biochim Biophys Acta 1813, 979-983   DOI
19 Soares MB, Bellintani MC, Ribeiro IM, Tomassini TC and Ribeiro dos Santos R (2003) Inhibition of macrophage activation and lipopolysaccaride-induced death by secosteroids purified from Physalis angulata L. Eur J Pharmacol 459, 107-112   DOI
20 Pinto LA, Meira CS, Villarreal CF et al (2016) Physalin F, a seco-steroid from Physalis angulata L., has immunosuppressive activity in peripheral blood mononuclear cells from patients with HTLV1-associated myelopathy. Biomed Pharmacother 79, 129-134   DOI
21 Yu Y, Sun L, Ma L, Li J, Hu L and Liu J (2010) Investigation of the immunosuppressive activity of Physalin H on T lymphocytes. Int Immunopharmacol 10, 290-297   DOI
22 Jacobo-Herrera NJ, Bremner P, Marquez N et al (2006) Physalins from Witheringia solanacea as modulators of the NF-kappaB cascade. J Nat Prod 69, 328-331   DOI
23 Sa MS, de Menezes MN, Krettli AU et al (2011) Antimalarial activity of physalins B, D, F, and G. J Nat Prod 74, 2269-2272   DOI
24 Yang YJ, Yi L, Wang Q, Xie BB, Dong Y and Sha CW (2017) Anti-inflammatory effects of physalin E from Physalis angulata on lipopolysaccharide-stimulated RAW 264.7 cells through inhibition of NF-kappaB pathway. Immunopharmacol Immunotoxicol 39, 74-79   DOI
25 Ding N, Wang Y, Dou C et al (2019) Physalin D regulates macrophage M1/M2 polarization via the STAT1/6 pathway. J Cell Physiol 234, 8788-8796   DOI
26 Liu Z, Guo F, Wang Y et al (2016) BATMAN-TCM: a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine. Sci Rep 6, 21146   DOI
27 Kim H, Kim T, Jeong BC et al (2013) Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation. Cell Metab 17, 249-260   DOI