Physalin D inhibits RANKL-induced osteoclastogenesis and bone loss via regulating calcium signaling
1
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
We investigated the effects of physalin A, B, D, and F on osteoclastogenesis induced by receptor activator of nuclear factor B 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 RANKLevoked intracellular calcium ([Ca(2＋)](i)) oscillation by inhibiting phosphorylation of phospholipase C2 (PLC2) and thus blocked the downstream activation of Ca2＋/calmodulindependent 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 PLC2-CaMK-CREB pathway.
Abstract
We investigated the effects of physalin A, B, D, and F on osteoclastogenesis induced by receptor activator of nuclear factor B 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 RANKLevoked intracellular calcium ([Ca(2＋)](i)) oscillation by inhibiting phosphorylation of phospholipase C2 (PLC2) and thus blocked the downstream activation of Ca2＋/calmodulindependent 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 PLC2-CaMK-CREB pathway.
참고문헌 (27)
- Yasuda H, "Osteoclast differentiation factor is a ligand for osteoprotegerin", osteoclastogenesis-inhibitory factor and is identical to TRANCE, Proc Nat Acad Sci U S A, pp.1998, 95[DOI]
- Hwang SY, "Calcium signaling in osteoclasts", Biochim Biophys Acta, 1813, pp.979~983 (2011)
- Li P, "Fluid flow-induced calcium response in osteoclasts : signaling pathways", Ann Biomed Eng, 42, pp.1250~1260 (2014)
- Hadjidakis DJ, "Bone remodeling", Ann New York Acad Sci, 1092, pp.385~396 (2006)
- Rodan GA, "Therapeutic approaches to bone diseases", Science, 289, pp.1508~1514 (2000)
- Bastos GN, "Physalis angulata extract exerts anti-inflammatory effects in rats by inhibiting different pathways", J Ethnopharmacol, 118, pp.246~251 (2008)
- Soares MB, "Inhibition of macrophage activation and lipopolysaccaride-induced death by secosteroids purified from Physalis angulata L", Eur J Pharmacol, 459, pp.107~112 (2003)
- Pinto LA, "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, pp.129~134 (2016)
- Yu Y, "Investigation of the immunosuppressive activity of Physalin H on T lymphocytes", Int Immunopharmacol, 10, pp.290~297 (2010)
- Jacobo-Herrera NJ, "Physalins from Witheringia solanacea as modulators of the NF-kappaB cascade", J Nat Prod, 69, pp.328~331 (2006)
- Sa MS, "Antimalarial activity of physalins B, D, F, and G", J Nat Prod, 74, pp.2269~2272 (2011)
- Yang YJ, "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, pp.74~79 (2017)
- Ding N, "Physalin D regulates macrophage M1", M2 polarization via the STAT1, J Cell Physiol, pp.2019, 234[DOI]
- Liu Z, "BATMAN-TCM : a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine", Sci Rep, 6, pp.21146~ (2016)
- Kim H, "Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation", Cell Metab, 17, pp.249~260 (2013)
- Takayanagi H, "Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nature reviews", Immunology, 7, pp.292~304 (2007)
- Wada T, "RANKL-RANK signaling in osteoclastogenesis and bone disease", Trends Mol Med, 12, pp.17~25 (2006)
- Tomimori Y, "Evaluation of pharmaceuticals with a novel 50-hour animal model of bone loss", J Bones Miner Res, 24, pp.1194~1205 (2009)
- Zheng Y, "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, pp.1278~1284 (2016)
- Liu H, "Two sulfonate metabolites of physalin A in rats", Xenobiotica, 48, pp.11~17 (2018)
- Hsu CC, "Physalin B from Physalis angulata triggers the NOXA-related apoptosis pathway of human melanoma A375 cells", Food Chem Toxicol, 50, pp.619~624 (2012)
- Vandenberghe I, "Physalin B, a novel inhibitor of the ubiquitin-proteasome pathway, triggers NOXA-associated apoptosis", Biochem Pharmacol, 76, pp.453~462 (2008)
- Chamoux E, "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, pp.25354~25362 (2010)
- Sato K, "Regulation of osteoclast differentiation and function by the CaMK-CREB pathway", Nat Med, 12, pp.1410~1416 (2006)
- Kajiya H, "Calcium signaling in osteoclast differentiation and bone resorption", Adv Exp Med Biol, 740, pp.917~932 (2012)
- Dou C, "MiR-7b directly targets DC-STAMP causing suppression of NFATc1 and c-Fos signaling during osteoclast fusion and differentiation", Biochim Biophys Acta, 1839, pp.1084~1096 (2014)
- Dou C, "Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway", Cell Death Dis, 7, pp.e2162~ (2016)