Abstract
Litsea cubeba (Lour.) Pers. (Lauraceae family) has been used as a folk prescription in China for the treatment of rheumatic diseases for a long time. Previous studies of our laboratory have indicated that 9′-O-di-(E)-feruloyl-meso-5, 5′-dimethoxy-secoisolariciresinol (FCL) which is a dibenzylbutane lignan enriched in L. cubeba displayed anti-inflammatory activity in LPS induced RAW264.7 cells. The present study was aimed to investigate anti-osteoporosis/anti-rheumatoid arthritis (RA) properties of FCL and explore its potential molecular targets. The anti-RA and anti-osteoporosis properties were evaluated by determination of cell proliferation, alkaline phosphatase (ALP) activity and calcium deposition formation on osteoblasts. Meanwhile, the Tartaric Resistnt Acid Phosphatase (TRAP) inhibitory activity of FCL was evaluated on the macrophage colony-stimulating factor (M-CSF) and soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) induced bone marrow cells (BMCs). Furthermore, molecular docking was carried out to predict the molecular targets of FCL, and cellular thermal shift assay (CETSA) was carried out to verify the in silico molecular docking results. The present results revealed that FCL promoted osteoblastogenesis and bone formation whereas suppressed osteoclastogenesis, and importantly, FCL showed strong binding activities to the cathepsin K and mitogen-activated proteinkinase kinase 1 (MEK1) based on the results of molecular docking and CETSA. Taken together, our results indicated that FCL may possess the anti-osteoporosis potential through acting on the targets of cathepsin K and MEK1.
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References
Alves CH, Farrell E, Vis M, Colin EM, Lubberts E (2016) Animal models of bone loss in inflammatory arthritis: from cytokines in the bench to novel treatments for bone loss in the bedside-a comprehensive review. Clin Rev Allergy Immunol 51:27–47
Balmanno K, Cook SJ (2009) Tumour cell survival signalling by the ERK1 2 pathway. Cell Death Differ 16:368–377
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342
Chang MC, Tsai YL, Chang HH, Lee SY, Lee MS, Chang CW, Chan CP, Yeh CY, Cheng RH, Jeng JH (2016) IL-1β-induced MCP-1 expression and secretion of human dental pulp cells is related to TAK1, MEKERK, and PI3KAkt signalling pathways. Arch Oral Biol 61:16–22
Chapurlat R (2016) Cathepsin K inhibitors and antisclerostin antibodies. Treat Osteoporos? Jt Bone Spine 83:254–256
Chapurlat RD, Confavreux CB (2016) Novel biological markers of bone: from bone metabolism to bone physiology. Rheumatol (Oxf) 55:1714–1725
Duong LT, Leung AT, Langdahl B (2016) Cathepsin K inhibition: a new mechanism for the treatment of osteoporosis. Calcif Tissue Int 98:381–397
Duong LT (2012) Therapeutic inhibition of cathepsin K-reducing bone resorption while maintaining bone formation. Bone Rep 1:67
Feng T, Xu Y, Cai XH, Du ZZ, Luo XD (2009) Antimicrobially active isoquinoline alkaloids from Litsea cubeba. Planta Med 75:76–79
Friday BB, Adjei AA (2008) Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res 14:342–346
Garnero P, Borel O, Byrjalsen I, Ferreras M, Drake FH, McQueney MS, Foged NT, Delmas PD, Delaissé JM (1998) The Collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 273:32347–32352
Hao L, Zhu G, Lu Y, Wang M, Jules Jl, Zhou X, Chen W (2015) Deficiency of cathepsin K prevents inflammation and bone erosion in rheumatoid arthritis and periodontitis and reveals its shared osteoimmune role. FEBS Lett 589:1331–1339
Hwang JK, Choi EM, Lee JH (2005) Antioxidant activity of Litsea cubeba. Fitoterapia 76:684–686
Kremers HM, Nicola P, Crowson CS, O’Fallon WM, Gabriel SE (2004) Ther-apeutic strategies in rheumatoid arthritis over a 40-year period. J Rheumatol 31:2366–2373
Kim SC, Solomon DH, Liu J, Franklin JM, Glynn RJ, Schneeweiss S (2015) Risk of venous thromboembolism in patients with rheumatoid arthritis: initiating disease-modifying antirheumatic drugs. Am J Med 128:539.e7–17
Lin B, Sun LN, Xin HL, Nian H, Song HT, Jiang YP, Wei ZQ, Qin LP, Han T (2016) Anti-inflammatory constituents from the root of Litsea cubeba in LPS-induced RAW 264.7 macrophages. Pharm Biol 54:1741–1747
Lin B, Zhang H, Zhao XX, Rahman K, Wang Y, Ma XQ, Zheng CJ, Zhang QY, Han T, Qin LP (2013) Inhibitory effects of the root extract of Litsea cubeba (lour.) pers. on adjuvant arthritis in rats. J Ethnopharmacol 147:327–334
Liagre B, Leger DY, Vergne-Salle P, Beneytout JL (2007) MAP kinase subtypes and Akt regulate diosgenin-induced apoptosis of rheumatoid synovial cells in association with COX-2 expression and prostanoid production. Int J Mol Med 19:113–122
Liu TT, Yang TS (2012) Antimicrobial impact of the components of essential oil of Litsea cubeba from Taiwan and antimicrobial activity of the oil in food systems. Int J Food Microbiol 156:68–75
Martinez MD, Jafari R, Ignatushchenko M, Seki T, Larsson EA, Dan C, Sreekumar L, Cao Y, Nordlund P (2013) Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science 341:84–87
McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219
Motyckova G, Fisher DE (2002) Pycnodysostosis: role and regulation of cathepsin K in osteoclast function and human disease. Curr Mol Med 2:407–421
Neidhart M, Baraliakos X, Seemayer C, Zelder C, Gay RE, Michel BA, Boehm H, Gay S, Braun J (2009) Expression of cathepsin K and matrix metalloproteinase 1 indicate persistent osteodestructive activity in long-standing ankylosing spondylitis. Ann Rheum Dis 68:1334–1339
Newman DJ, Cragg GM (2016) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79:629–661
Novinec M, Lenarčič B (2013) Cathepsin K: a unique collagenolytic cysteine peptidase. Biol Chem 394:1163–1179
Ohori M (2008) ERK inhibitors as a potential new therapy for rheumatoid arthritis. Drug News Perspect 21:245–250
Pettit AR, Walsh NC, Manning C, Goldring SR, Gravallese EM (2006) RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology 45:1068–1076
Svelander L, Erlandsson-Harris H, Astner L, Grabowska U, Klareskog L, Lindstrom E (2009) Inhibition of cathepsin K reduces bone erosion, cartilage degradation and inflammation evoked by collagen-induced arthritis in mice. Eur J Pharmacol 613:155–162
Thiel MJ, Schaefer CJ, Lesch ME, Mobley JL, Dudley DT, Tecle H, Barrett SD, Schrier DJ, Flory CM (2007) Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms. Arthritis Rheum 56:3347–3357
Wang Y, Zhao L, Wang Y, Xu J, Nie Y, Guo Y, Tong Y, Qin L, Zhang Q (2012) Curculigoside isolated from Curculigo orchioides prevents hydrogen peroxide-induced dysfunction and oxidative damage in calvarial osteoblasts. Acta Biochim Biophys Sin (Shanghai) 44:431–441
Wittrant Y, Couillaud S, Theoleyre S, Dunstan C, Heymann D, Rédini F (2002) Osteoprotegerin differentially regulates protease expression in osteoclast cultures. Biochem Biophys Res Commun 293:38–44
Xu H, Gopalsamy A, Hett EC, Salter S, Aulabaugh A, Kyne RE, Pierce B, Jones LH (2016) Cellular thermal shift and clickable chemical probe assays for the determination of drug-target engagement in live cells. Org Biomol Chem 14:6179–6183
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This work was supported by the National Natural Science Foundation of China (Grant No. 81573696) and the Foundation of Science and Technology Commission of Shanghai (Grant No. 14401902900).
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These authors contributed equally: Wei Peng, Hui Shen.
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Peng, W., Shen, H., Lin, B. et al. Docking study and antiosteoporosis effects of a dibenzylbutane lignan isolated from Litsea cubeba targeting Cathepsin K and MEK1. Med Chem Res 27, 2062–2070 (2018). https://doi.org/10.1007/s00044-018-2215-8
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DOI: https://doi.org/10.1007/s00044-018-2215-8