title: Ginsenoside metabolite compound K exerts joint-protective effect by interfering with synoviocyte function mediated by TNF-α and Tumor necrosis factor receptor type 2.
abstract: Ginsenoside metabolite compound K (CK), metabolite of the ginsenoside, is considered to exert numerous pharmacological efficacies of ginsenoside, including anti-inflammation and immunoregulatory effects. Rheumatoid arthritis (RA) is a multi-systemic autoimmune disease characterized by hyperplastic synovial membrane and systemic inflammation, which ultimately lead to progressive destructive inflammatory arthropathy. To evaluate the potential joint-protective effects of CK and the underlying mechanism, adjuvant arthritis (AA) was induced by complete Freund's adjuvant in rats. After the onset of arthritis, The effect of CK on AA rats was evaluated by histopathology of the joint. The proliferation of fibroblast-like synoviocyte(FLS) was assayed by the Cell Counting Kit-8.The migration of FLS was assayed by transwell migration assay. Cytokines in the supernatant from FLS were measured by ELISA kit. Expression of Tumor Necrosis Factor Receptor Type 1(TNFR1) and Tumor Necrosis Factor Receptor Type 2(TNFR2) were detected by immunostaining analysis and western blot analysis. CK (80mg/kg) significantly ameliorated the histopathological change of joint in AA rats, balanced the RANKL/OPG ratio and attenuated the proliferation and migration of AA-FLS. CK suppressed the secretion of proinflammatory cytokines TNF-α and downregulated the expression of TNFR2 on AA-FLS. In vitro CK also significantly suppressed proliferation, migration and secretion of AA-FLS mediated by TNF-α. Further studies showed that the effects of CK on AA-FLS were reversed by using glucocorticoid receptor (GR) antagonist (mifepristone). Our data suggest that CK exerts joint-protective effect by interfering with synoviocyte function mediated by TNF-α and TNFR2, and this effect may be mediated by GR.
authors.affiliation: Institute of Clinical Pharmacology of Anhui Medical University, key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei 230032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology of Anhui Medical University, key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei 230032, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Clinical Pharmacology of Anhui Medical University, key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei 230032, China.
authors.forename: Xuexia
authors.initials: X
authors.lastname: Luo
authors.affiliation: Institute of Clinical Pharmacology of Anhui Medical University, key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei 230032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacology of Anhui Medical University, key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei 230032, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Si
authors.affiliation: Institute of Clinical Pharmacology of Anhui Medical University, key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei 230032, China.
authors.forename: Huaxun
authors.initials: H
authors.lastname: Wu
authors.affiliation: Institute of Clinical Pharmacology of Anhui Medical University, key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei 230032, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Yan
authors.affiliation: Institute of Clinical Pharmacology of Anhui Medical University, key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei 230032, China. Electronic address: wwei@ahmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000096:biosynthesis*; D012502:Sapogenins / Q000494:pharmacology*; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: C482402:20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol; D000893:Anti-Inflammatory Agents; D006727:Hormone Antagonists; D053245:RANK Ligand; D011965:Receptors, Glucocorticoid; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012502:Sapogenins; C506237:Tnfrsf1a protein, rat; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone
keywords: Adjuvant arthritis; Fibroblast-like synoviocyte; Ginsenoside metabolite compound K; Glucocorticoid receptor; TNF-α; Tumor necrosis factor receptor