XIONG Xue-ting,XU Bi-lian.Research progress of Wnt signaling pathway in pathogenesis of rheumatoid arthritis[J].Chinese Pharmacological Bulletin,2014,(01):13-16.





Research progress of Wnt signaling pathway in pathogenesis of rheumatoid arthritis
2.广东天然药物研究与开发重点实验室,广东 湛江524023
XIONG Xue-ting XU Bi-lian
1.Dept of Pharmacology, Guangdong Medical College;
2.Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical College, Zhanjiang Guangdong524023, China
rheumatoid arthritis Wnt signaling pathway bone destruction cartilage destruction osteoclast osteoblast
类风湿性关节炎(rheumatoid arthritis,RA)被喻为是不死的癌症,因其发病过程累及多系统,涉及的细胞因子、蛋白等生物分子众多,故其具体的发病机制至今仍未阐明。近年来,Wnt通路在RA中对炎症、软骨和骨等方面发挥的作用逐渐被证实,这些发现不仅为深入研究RA的发病机制提供新思路,而且为防治RA疾病的药物研究提供了新靶点。
Rheumatoid arthritis(RA) is defined as deathless cancer. The specific mechanism still remains to be expounded, as it involes several systems and a lot of cytokines, proteins, etc. In recent years, roles of Wnt signaling pathway in inflammation, cartilage, bone and other aspects in RA have been clarified gradually. These findings not only provide new thinking for deep exploration in pathogenesis of RA, but also offer novel target spots for drug developing in preventing RA.


[1]邱贵兴, 史占军,吕厚山,等. 类风湿关节炎的诊断与治疗骨科专家共识[J]. 中国医学前沿杂志, 2013, 5(3): 49-52. [1]Qiu G X, Shi Z J, Lv H S, et al. Consensus of orthopedic specialists in rheumatoid arthritis diagnosis and treatment[J]. Chin J Front Med Sci, 2013, 5(3): 49-52.
[2]Antara D. Wnt/Ca2+ signaling pathway: a brief overview[J]. Acta Biochim Biophys Sin, 2011, 43(10):745-56.
[3]Yang D H,Yoon J Y,Lee S H, et al. Wnt5a is required for endothelial differentiation of embryonic stem cells and vascularization via pathways involving both Wnt/beta-catenin and protein kinase Calpha[J]. Circulat Res, 2009, 104(3):372-9.
[4]Mezzacappa C, Komiya Y, Habas R. Activation and function of small GTPases Rho, Rac, and Cdc42 during gastrulation[J]. Methods Mole Biol, 2012, 839:119-31.
[5]Xiao C Y, Pan Y F, Guo X H, et al. Expression of β-catenin in rheumatoid arthritis fibroblast-like synoviocytes[J]. Scand J Rheumatol, 2011, 40(1):26-33.
[6]Krause U, Gregory C A. Potential of modulating Wnt signaling pathway toward the development of bone anabolic agent[J]. Curr Mol Pharmacol, 2012, 5(2):164-73.
[7]Matzelle M M, Gallant M A, Condon K W, et al. Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway[J]. Arthritis Rheum, 2012, 64(5):1540-50.
[8]Cheon H, Boyle D L, Firestein G S. Wnt1 inducible signaling pathway protein-3 regulation and microsatellite structure in arthritis[J]. J Rheumatol, 2004, 31(11):2106-14
[9]Kim J, Kim D W, Ha Y, et al. Wnt5a induces endothelial inflammation via beta-catenin-independent signaling[J]. J Immunol, 2010, 185(2):1274-82.
[10]Sen M, Chamorro M, Reifert J, et al. Blockade of Wnt-5A/frizzled 5 signaling inhibits rheumatoid synoviocyte activation[J]. Arthritis Rheum, 2001, 44(4): 772-81.
[11]Rauner M, Stein N, Winzer M, et al. WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production[J]. J Bone Miner Res, 2012, 27(3):575-85.
[12]缪成贵,黄成,黄艳,等. Wnt调控类风湿性关节炎研究进展[J]. 中国药理学通报, 2013, 29(2):149-53.
[12]Miao C G, Huang C, Huang Y, et al. Research progress of the Wnt in rheumatoid arthritis[J]. Chin Pharmacol Bull, 2013, 29(2):149-53.
[13]Weaver C T, Harrington L E, Mangan P R, et al. Th17: an effector CD4 T cell lineage with regulatory T cell ties[J]. Immunity, 2006, 24(6):677-765.
[14]Yuasa T, Otani T, Koike T, et al. Wnt/beta-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes:its possible role in joint degeneration[J]. Lab Invest, 2008, 88(3):264-74.
[15]Zhu M, Chen M, Zuscik M, et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction[J]. Arthritis Rheum, 2008, 58(7): 2053-64.
[16]Sen M, Lauterbach K, El-Gabalawy H, et al. Expression and function of wingless and frizzled homologs in rheumatoid arthritis[J]. Proc Natl Acad Sci USA, 2000, 97(6):2791-6.
[17]Ma B, Landman E B, Miclea R L, et al. WNT signaling and cartilage: of mice and men[J]. Calcif Tissue Int, 2013, 92(5):399-411.
[18]Bultink I E, Vis M, van der Horst-Bruinsma I E, et al. Inflammatory rheumatic disorders and bone[J]. Curr Rheumatol Rep, 2012, 14(3):224-30.
[19]Walsh N C, Gravallese E M. Bone remodeling in rheumatic disease: a question of balance[J]. Immunol Rev, 2010, 233(1):301-12.
[20]Wang S Y, Liu Y Y, Ye H, et al. Circulating Dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis[J]. J Rheumatol, 2011, 38(5);821-7.
[21]Lee J H, Kim B G, Ahn J M, et al. Role of PI3K on the regulation of BMP2-induced beta-Catenin activation in human bone marrow stem cells[J]. Bone, 2010, 46(6):1522-32.
[22]Babii P, Zhao W, Small C, er al. High bone mass in mice expressing a mutant LRP5 gene[J]. J Bone Miner Res, 2003, 18(6):960-74.
[23]Sonomoto K, Yamaoka K, Oshita K, et al. Interleukin-1β induces differentiation of human mesenchymal stem cells into osteoblasts via the Wnt-5a/receptor tyrosine kinase-like orphan receptor 2 pathway[J]. Arthritis Rheum, 2012, 64(10):3355-63.
[24]Cheng S L, Shao J S, Cai J, et al. Msx2 exerts bone anabolism via canonical Wnt signaling[J]. J Boil Chem, 2008, 283(29):20505-22.
[25]MacDonald B T, Joiner D M, Oyserman S M, et al. Bone mass is inversely proportional to DKK1 levels in mice[J]. Bone, 2007, 41(3):331-40.
[26]de Rooy D P, Yeremenko N G, Wilson A G, et al. Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis[J]. Annals Rheumat Dis, 2013, 72(5):769-75.
[27]Daoussis D, Andonopoulos A P, Liossis S N. Wnt pathway and IL-17: novel regulators of joint remodeling in rheumatic diseases. Looking beyond the RANK-RANKL-OPG axis[J]. Semin Arthritis Rheum,2010, 39(5):369-83.
[28]Bodine P V, Zhao W, Kharode Y P, et al. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice[J]. Mol Endocrinol, 2004, 18(5):1222-37.
[29]Corr M, Lane N E. FRZB: a bone and joint connection[J]. Arthritis Rheum, 2007, 56(12):3881-3.
[30]Spencer G J, Utting J C, Etheridge S L, et al. Wnt signalling in osteoblasts regulates expression of the receptor activator of NKkappaB ligand and inhibits osteoclastogenesis in vitro[J]. J Cell Sci, 2006, 119(Pt7):1283-96.
[31]Glass D A 2nd, Bialek P, Ahn J D, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation[J]. Dev Cell, 2005, 8(5):751-64.
[32]Fujita K, Janz S. Attenuation of WNT signaling by DKK-1 and-2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF[J]. Mol Cancer, 2007, 30(6):71.
[33]Maeda K, Takahashi N, Kobayashi Y. Roles of Wnt signals in bone resorption during physiological and pathological states[J].Mol Med, 2013, 91(1):15-23.
[34]Yang Y, Topol L, Lee H, et al. Wnt5a anf Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation[J]. Development, 2003, 130(5):1003-15.
[35]Katoh M, Katoh M. STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer[J]. Int J Mol Med, 2007, 19(2):273-8.
[36]Hausler K D, Horwood N J, Chuman Y, et al. Secreted frizzled-related protein-1 inhibits RANKL-dependent osteoclast formation[J]. J Bone Miner Res, 2004, 19(11):1873-954.


 ZHAO Xiao hui,YUE Hui lan,MEI Li juan,et al.The effects of Myospalax fontanieri extracts on cattle type Ⅱcollageninduced arthritis[J].Chinese Pharmacological Bulletin,2008,(01):0.
 WANG Ting yu,LI Jun.Progress of CD4+CD25+ regulatory T cells in rheumatoid arthritis[J].Chinese Pharmacological Bulletin,2008,(01):0.
 HUANG Xue ying,CHEN Fei hu,ZHANG Xiao ming,et al.Endostatin: antiangiogenic properties and the therapeutic effect on rheumatoid arthritis[J].Chinese Pharmacological Bulletin,2009,(01):0.
 ZHANG Li,WAN Jing yuan,YE Du yun,et al.Lipoxin receptor agonist BML111 alleviates adjuvant arthritis in rats[J].Chinese Pharmacological Bulletin,2009,(01):0.
 LI Xia,YUAN Feng lai,ZHAO Yi qing,et al.Role of osteopontin in rheumatoid arthritis[J].Chinese Pharmacological Bulletin,2012,(01):155.
 FU Jing jing,ZHANG Ling ling,WEI Wei.Dual role of dendritic cells in the pathological mechanism of rheumatoid arthritis: immunogenicity and tolerogenicity[J].Chinese Pharmacological Bulletin,2012,(01):1185.
 MIAO Cheng gui,HUANG Cheng,HUANG Yan,et al.Research progress of the Wnt in rheumatoid arthritis[J].Chinese Pharmacological Bulletin,2013,(01):149.
 YANG Jin na,LIU Xiao guang,LI Tan,et al.Function of Th17/Treg balance in rheumatoid arthritis[J].Chinese Pharmacological Bulletin,2013,(01):1045.
[9]吴青云,熊雪婷,许碧莲,等.泼尼松对Ⅱ型胶原诱导性关节炎大鼠 股骨微结构及生物力学的影响[J].中国药理学通报,2014,(07):1018.
 WU Qing-yun,XIONG Xue-ting,XU Bi-lian,et al.Effects of prednisone on trabecular microstructure and biomechanical properties of femur in a rat model of type II collagen-induced arthritis[J].Chinese Pharmacological Bulletin,2014,(01):1018.
[10]马钰泱,狄泽敏,曹 晴,等.佐剂性关节炎大鼠滑膜及血清中MANF的表达及其与炎症的相关性[J].中国药理学通报,2018,(04):537.[doi:10.3969/j.issn.1001-1978.2018.04.020]
 MA Yu-yang,DI Ze-min,CAO Qing,et al.Expression characterization of MANF during course of rat adjuvant arthritis and its relationship with inflammation[J].Chinese Pharmacological Bulletin,2018,(01):537.[doi:10.3969/j.issn.1001-1978.2018.04.020]


基金项目:国家自然科学基金面上项目(No 81373499);广东省科技计划项目(No 2011B031800248)
作者简介:熊雪婷(1989-),女,硕士生,E-mail:13763045727@163.com; 许碧莲(1970-),女,硕士,副教授,硕士生导师,研究方向:骨质疏松的药物防治,Tel: 0759-2388588,Fax:0759-2284104, E-mail:gdmcxu@126.com
更新日期/Last Update: 2014-01-15