Ginsenoside Rg2 inhibits osteoclastogenesis by downregulating the NFATc1, c-Fos, and MAPK pathways
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Ginsenosides, among the most active components of ginseng,exhibit several therapeutic effects against cancer, diabetes, andother metabolic diseases. However, the molecular mechanismunderlying the anti-osteoporotic activity of ginsenoside Rg2, amajor ginsenoside, has not been clearly elucidated. This studyaimed to determine the effects of ginsenoside Rg2 on receptoractivator of nuclear factor-κB ligand (RANKL)-induced osteoclastformation. Results indicate that ginsenoside Rg2 inhibits RANKLinducedosteoclast differentiation of bone marrow macrophages(BMMs) without cytotoxicity. Pretreatment with ginsenoside Rg2significantly reduced the RANKL-induced gene expression ofc-fos and nuclear factor of activated T-cells (Nfatc1), as well asosteoclast-specific markers tartrate-resistant acid phosphatase(TRAP, Acp5) and osteoclast-associated receptor (Oscar). Moreover,RANKL-induced phosphorylation of mitogen-activated proteinkinases (MAPKs) was decreased by ginsenoside Rg2 in BMM. Therefore, we suggest that ginsenoside Rg2 suppresses RANKLinducedosteoclast differentiation through the regulation of MAPKsignaling-mediated osteoclast markers and could be developedas a therapeutic drug for the prevention and treatment of osteoporosis.
Abstract
Ginsenosides, among the most active components of ginseng,exhibit several therapeutic effects against cancer, diabetes, andother metabolic diseases. However, the molecular mechanismunderlying the anti-osteoporotic activity of ginsenoside Rg2, amajor ginsenoside, has not been clearly elucidated. This studyaimed to determine the effects of ginsenoside Rg2 on receptoractivator of nuclear factor-κB ligand (RANKL)-induced osteoclastformation. Results indicate that ginsenoside Rg2 inhibits RANKLinducedosteoclast differentiation of bone marrow macrophages(BMMs) without cytotoxicity. Pretreatment with ginsenoside Rg2significantly reduced the RANKL-induced gene expression ofc-fos and nuclear factor of activated T-cells (Nfatc1), as well asosteoclast-specific markers tartrate-resistant acid phosphatase(TRAP, Acp5) and osteoclast-associated receptor (Oscar). Moreover,RANKL-induced phosphorylation of mitogen-activated proteinkinases (MAPKs) was decreased by ginsenoside Rg2 in BMM. Therefore, we suggest that ginsenoside Rg2 suppresses RANKLinducedosteoclast differentiation through the regulation of MAPKsignaling-mediated osteoclast markers and could be developedas a therapeutic drug for the prevention and treatment of osteoporosis.
참고문헌 (43)
- Novack DV, "The osteoclast : friend or foe?", Annu Rev Pathol, 3, pp.457~484 (2008)
- Nakashima T, "Evidence for osteocyte regulation of bone homeostasis through RANKL expression", Nat Med, 17, pp.1231~1234 (2011)
- Rodan GA, "Therapeutic approaches to bone diseases", Science, 289, pp.1508~1514 (2000)
- Rivollier A, "Immature dendritic cell transdifferentiation into osteoclasts : a novel pathway sustained by the rheumatoid arthritis microenvironment", Blood, 104, pp.4029~4037 (2004)
- Roodman GD, "Cell biology of the osteoclast", Exp Hematol, 27, pp.1229~1241 (1999)
- Takeshita S, "SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts", Nat Med, 8, pp.943~949 (2002)
- Genant HK, "Estrogens in the prevention of osteoporosis in postmenopausal women", Am J Obstet Gynecol, 161, pp.1842~1846 (1989)
- Reid IR, "Pharmacotherapy of osteoporosis in postmenopausal women : focus on safety", Expert Opin Drug Saf, 1, pp.93~107 (2002)
- Kong YY, "OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis", Nature, 397, pp.315~323 (1999)
- Lee ZH, "Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts", Biochem Biophys Res Commun, 305, pp.211~214 (2003)
- Lee SE, "The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation", Bone, 30, pp.71~77 (2002)
- Li J, "RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism", Proc Natl Acad Sci U S A, 97, pp.1566~1571 (2000)
- Walsh MC, "Osteoimmunology : interplay between the immune system and bone metabolism", Annu Rev Immunol, 24, pp.33~63 (2006)
- Chang Y, "Ginsenosides Rg1 and Rb1 enhance glutamate release through activation of protein kinase A in rat cerebrocortical nerve terminals(synaptosomes)", Eur J Pharmacol, 578, pp.28~36 (2008)
- Chen WF, "Activation of insulin-like growth factor I receptormediated pathway by ginsenoside Rg1", Br J Pharmacol, 147, pp.542~551 (2006)
- Lau WS, "Ginsenoside Rg1 exerts estrogen-like activities via ligand-independent activation of ERalpha pathway", J Steroid Biochem Mol Biol, 108, pp.64~71 (2008)
- Pan XY, "Ginsenoside Rg3attenuates cell migration via inhibition of aquaporin 1expression in PC-3M prostate cancer cells", Eur J Pharmacol, 683, pp.27~34 (2012)
- Kim HR, "Effect of ginseng mixture on osteoporosis in ovariectomized rats", Immunopharmacol Immunotoxicol, 30, pp.333~345 (2008)
- Liu J, "20(R)-ginsenoside Rh2, not 20(S), is a selective osteoclastgenesis inhibitor without any cytotoxicity", Bioorg Med Chem Lett, 19, pp.3320~3323 (2009)
- Yuan HD, "Ginsenoside Rg2 induces orphan nuclear receptor SHP gene expression and inactivates GSK3beta via AMP-activated protein kinase to inhibit hepatic glucose production in HepG2 cells", Chem Biol Interact, 195, pp.35~42 (2012)
- Zhang G, "Panax ginseng ginsenoside-Rg2 protects memory impairment via anti-apoptosis in a rat model with vascular dementia", J Ethnopharmacol, 115, pp.441~448 (2008)
- Qianqian Xue, "Protective effect and mechanism of ginsenoside Rg2 on atherosclerosis", Journal of Ginseng Research, 47(2), pp.237~245 (2023), 고려인삼학회
- Zhou L, "SIRT5 promotes IDH2desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense", EMBO Rep, 17, pp.811~822 (2016)
- Yao F, "Phenolic compounds and ginsenosides in ginseng shoots and their antioxidant and anti-inflammatory capacities in LPS-induced RAW264. 7 mouse macrophages", Int J Mol Sci, 20, pp.2951~ (2019)
- Wang ZQ, "Bone and haematopoietic defects in mice lacking c-fos", Nature, 360, pp.741~745 (1992)
- Takayanagi H, "Induction and activation of the transcription factor NFATc1(NFAT2)integrate RANKL signaling in terminal differentiation of osteoclasts", Dev Cell, 3, pp.889~901 (2002)
- Lee JH, "Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-kappaB signal", Mol Pharmacol, 77, pp.17~25 (2010)
- Nedeva IR, "Role of OSCAR signaling in osteoclastogenesis and bone disease", Front Cell Dev Biol, 9, pp.641162~ (2021)
- Kim HN, "Anti-inflammatory effect of Vaccinium oldhamii stems through inhibition of NF-kappaB and MAPK", ATF2 signaling activation in LPSstimulated RAW264. 7 cells, 2019, pp.19, 291~
- Teitelbaum SL, "Genetic regulation of osteoclast development and function", Nat Rev Genet, 4, pp.638~649 (2003)
- Teitelbaum SL, "RANKing c-Jun in osteoclast development", J Clin Invest, 114, pp.463~465 (2004)
- Kiefer D, "Panax ginseng", Am Fam Physician, 68, pp.1539~1542 (2003)
- Grigoriadis AE, "c-Fos : a key regulator of osteoclast-macrophage lineage determination and bone remodeling", Science, 266, pp.443~448 (1994)
- Yamashita T, "NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand(RANKL)and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1", J Biol Chem, 282, pp.18245~18253 (2007)
- Wagner EF, "Fos", AP-1 proteins in bone and the immune system, 2005, pp.208, 126~140
- Gohda J, "RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis", EMBO J, 24, pp.790~799 (2005)
- Takayanagi H, "Osteoimmunology : shared mechanisms and crosstalk between the immune and bone systems", Nat Rev Immunol, 7, pp.292~304 (2007)
- Boyle WJ, "Osteoclast differentiation and activation", Nature, 423, pp.337~342 (2003)
- Ang E, "Mangiferin attenuates osteoclastogenesis, bone resorption, and RANKL-induced activation of NF-kappaB and ERK", J Cell Biochem, 112, pp.89~97 (2011)
- Kim HJ, "Suppression of osteoclastogenesis by N, N-dimethyl-D-erythro-sphingosine : a sphingosine kinase inhibition-independent action", Mol Pharmacol, 72, pp.418~428 (2007)
- Monje P, "Regulation of the transcriptional activity of c-Fos by ERK. A novel role for the prolyl isomerase PIN1", J Biol Chem, 280, pp.35081~35084 (2005)
- Ikeda F, "Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation", J Clin Invest, 114, pp.475~484 (2004)
- Matsumoto M, "Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand(RANKL)", J Biol Chem, 275, pp.31155~31161 (2000)
