Volume 4, Issue 1, February 2019     |     PP. 1-15      |     PDF (1739 K)    |     Pub. Date: March 23, 2019
DOI:    349 Downloads     5055 Views  


Lyudmila Belenska-Todorova, Medical Faculty, Sofia University, Bulgaria
Petya Ganova, Institute of Microbiology, Department of Immunology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
Nina Ivanovska, Institute of Microbiology, Department of Immunology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria

Berberine is a protoberberine alkaloid possessing various pharmacological activities, known as a Janus kinase (JAK) inhibitor. The aim of the present study was to elucidate the mechanism of its action in relation to JAK2/3 and sclerostin expression in synovium and cartilage, the presence of Receptor activator of factor kΒ Ligand (RANKL) positive cells in synovial fluid, the presence of dendritic cells (DC) in cartilage and the expression of TNF-related apoptosis-inducing ligand (TRAIL) and its receptor DR5 on bone marrow (BM) cells. The experiments were conducted in a mouse model of erosive inflammatory joint disease, relevant to human rheumatoid arthritis, induced through intraarticular injection of zymosan. Berberine decreased the phosphorilation of both JAK2 and JAK3 in arthritic joints, the expression of RANKL, TRAIL and DR5. The alkaloid did not affect sclerostin expression and prevented the decrease of the number of 33D1 positive dendritic cells. Present results contribute to more clear understanding of the ameliorative effect of berberine on erosive processes in joint inflammation.

berberine, JAK inhibitors, erosive arthritis, dendritic cells

Cite this paper
Lyudmila Belenska-Todorova, Petya Ganova, Nina Ivanovska, IN VIVO ELUCIDATION OF ANTI-ARTHRITIC EFFECT OF PLANT ALKALOID BERERINE IN EXPERIMENTAL MOUSE JOINT INFLAMMATION , SCIREA Journal of Biology. Volume 4, Issue 1, February 2019 | PP. 1-15.


[ 1 ] Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356-61.
[ 2 ] Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-81.
[ 3 ] Araki Y, Mimura T. The Mechanisms Underlying Chronic Inflammation in Rheumatoid Arthritis from the Perspective of the Epigenetic Landscape. J Immunol Res. 2016;2016:6290682.
[ 4 ] Calabresi E, Petrelli F, Bonifacio AF, Puxeddu I, Alunno A. One year in review 2018: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 2018;36(2):175-84.
[ 5 ] Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell. 1996;85(3):307-10.
[ 6 ] Hopkins SJ, Meager A. Cytokines in synovial fluid: II. The presence of tumour necrosis factor and interferon. Clin Exp Immunol. 1988;73(1):88-92.
[ 7 ] Mateen S, Moin S, Shahzad S, Khan AQ. Level of inflammatory cytokines in rheumatoid arthritis patients: Correlation with 25-hydroxy vitamin D and reactive oxygen species. PLoS One. 2017;12(6):e0178879.
[ 8 ] Alunno A. Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets. BMC Rheumatology. 2017;1(3):1-13.
[ 9 ] Okamoto H, Kobayashi A. Tyrosine kinases in rheumatoid arthritis. J Inflamm (Lond). 2011;8:21.
[ 10 ] Ghoreschi K, Laurence A, O'Shea JJ. Selectivity and therapeutic inhibition of kinases: to be or not to be? Nat Immunol. 2009;10(4):356-60.
[ 11 ] Kawamura M, McVicar DW, Johnston JA, Blake TB, Chen YQ, Lal BK, et al. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci U S A. 1994;91(14):6374-8.
[ 12 ] Walker JG, Smith MD. The JAK-STAT pathway in rheumatoid arthritis. J Rheumatol. 2005;32(9):1650-3.
[ 13 ] Jiang JK, Ghoreschi K, Deflorian F, Chen Z, Perreira M, Pesu M, et al. Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-y l)-3-oxopropanenitrile (CP-690,550). J Med Chem. 2008;51(24):8012-8.
[ 14 ] Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60(7):1895-905.
[ 15 ] Kotyla PJ. Are Janus Kinase Inhibitors Superior over Classic Biologic Agents in RA Patients? Biomed Res Int. 2018;2018:7492904.
[ 16 ] Fleischmann R, Kremer J, Tanaka Y, Gruben D, Kanik K, Koncz T, et al. Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies. Int J Rheum Dis. 2016;19(12):1216-25.
[ 17 ] van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA, Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508-19.
[ 18 ] Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales L, Reyes Gonzaga J, et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med. 2017;376(7):652-62.
[ 19 ] Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, et al. Disruption of the JAK1 gene demonstrates obligatory and nonredundant roles of the JAKs in cytokine-induced biologic responses. Cell. 1998;93(3):373-83.
[ 20 ] Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K. JAK2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell. 1998;93(3):397-409.
[ 21 ] Alamgeer, Uttra AM, Hasan UH. Anti-arthritic activity of aqueous-methanolic extract and various fractions of Berberis orthobotrys Bien ex Aitch. BMC Complement Altern Med. 2017;17(1):371.
[ 22 ] Kumar R, Gupta YK, Singh S. Anti-inflammatory and anti-granuloma activity of Berberis aristata DC. in experimental models of inflammation. Indian J Pharmacol. 2016;48(2):155-61.
[ 23 ] Ivanovska N, Philipov S. Study on the anti-inflammatory action of Berberis vulgaris root extract, alkaloid fractions and pure alkaloids. Int J Immunopharmacol. 1996;18(10):553-61.
[ 24 ] Kim BH, Kim M, Yin CH, Jee JG, Sandoval C, Lee H, et al. Inhibition of the signalling kinase JAK3 alleviates inflammation in monoarthritic rats. Br J Pharmacol. 2011;164(1):106-18.
[ 25 ] Zhao GL, Yu LM, Gao WL, Duan WX, Jiang B, Liu XD, et al. Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress. Acta Pharmacol Sin. 2016;37(3):354-67.
[ 26 ] Gomez-Puerta JA, Mocsai A. Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Curr Top Med Chem. 2013;13(6):760-73.
[ 27 ] Ganova P, Belenska-Todorova L, Doncheva T, Ivanovska N. Berberine prevents bone and cartilage destruction and influences cell senescence in experimental arthritis. J Adv Med Pharm Sci. 2017;3(15):1-8.
[ 28 ] Ganova P, Belenska-Todorova L, Gyurkovska V, Ivanovska N. Potential targets of kinase inhibitors in rheumatoid arthritis. In: Treatment options for rheumatoid arthritis. Editor, 2018. p. 1-44.
[ 29 ] Wang X, He X, Zhang CF, Guo CR, Wang CZ, Yuan CS. Anti-arthritic effect of berberine on adjuvant-induced rheumatoid arthritis in rats. Biomed Pharmacother. 2017;89:887-93.
[ 30 ] Wang XH, Jiang SM, Sun QW. Effects of berberine on human rheumatoid arthritis fibroblast-like synoviocytes. Exp Biol Med (Maywood). 2011;236(7):859-66.
[ 31 ] Ivanovska N, Philipov S, Hristova M. Influence of berberine on T-cell mediated immunity. Immunopharmacol Immunotoxicol. 1999;21(4):771-86.
[ 32 ] Kamiya N, Ye L, Kobayashi T, Mochida Y, Yamauchi M, Kronenberg HM, et al. BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development. 2008;135(22):3801-11.
[ 33 ] Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998;95(7):3597-602.
[ 34 ] Shaw AT, Gravallese EM. Mediators of inflammation and bone remodeling in rheumatic disease. Semin Cell Dev Biol. 2016;49:2-10.
[ 35 ] Yu MB, Langridge WHR. The function of myeloid dendritic cells in rheumatoid arthritis. Rheumatol Int. 2017;37(7):1043-51.
[ 36 ] Rodriguez-Fernandez JL. Antigen presentation by dendritic cells in rheumatoid arthritis. Curr Top Med Chem. 2013;13(6):712-9.
[ 37 ] Almasan A, Ashkenazi A. Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev. 2003;14(3-4):337-48.
[ 38 ] Ichikawa K, Liu W, Fleck M, Zhang H, Zhao L, Ohtsuka T, et al. TRAIL-R2 (DR5) mediates apoptosis of synovial fibroblasts in rheumatoid arthritis. J Immunol. 2003;171(2):1061-9.
[ 39 ] Narducci P, Bareggi R, Nicolin V. Interaction of human recombinant tumor necrosis factor-related apoptosis-inducing ligand and osteoprotegerin could contribute to enhancement of the erosive processes induced by human synovial cells. J Rheumatol. 2009;36(8):1837-9.
[ 40 ] Pettersen I, Figenschau Y, Olsen E, Bakkelund W, Smedsrod B, Sveinbjornsson B. Tumor necrosis factor-related apoptosis-inducing ligand induces apoptosis in human articular chondrocytes in vitro. Biochem Biophys Res Commun. 2002;296(3):671-6.