6-Shogaol inhibits chondrocytes' innate immune responses and cathepsin-K activity.

SCOPE Ginger has long been used in traditional Asian medicine to treat osteoarthritis. Indeed, scientific research has reported that ginger derivatives (GDs) have the potential to control innate immune responses. Given the widespread use and demonstrated properties of GDs, we set out to study their anti-inflammatory and anticatabolic properties in chondrocytes. METHODS AND RESULTS 6-shogaol (6-S), the most active GD, was obtained from ginger. 6-S was not toxic as measured by MTT assay, and inhibited NO production and IL-6 and MCP-1 induced gene expression in LPSbut not in IL-1β-stimulated chondrocytes. 6-S also inhibited LPS-mediated ERK1/2 activation as well as NOS2 and MyD88 induced expression as determined by Western blot. Moreover, zymography revealed that 6-S inhibited matrix metalloproteinases (MMP) 2/9 induction in LPS-treated cells. Hydrated 6-S was modified to obtain a compound (SSi6) without 6-S potential anti-inflammatory properties. Both 6-S and SSi6 inhibited cathepsin-K activity. CONCLUSION 6-S blocked TLR4-mediated innate immune responses and MMP induction in chondrocytes. These results, together with GDs-mediated cathepsin-K inhibition, suggest the potential for GDs use against cartilage and bone degradation. Therefore, considering that clinical trials involving oral administration of ginger achieved relevant nontoxic GDs serum concentrations, we suggest that a ginger-supplemented diet might reduce OA symptoms.

[1]  M. Puszczewicz,et al.  Fatigue and interleukin-6 – a multi-faceted relationship , 2015, Reumatologia.

[2]  G. Herrero-Beaumont,et al.  TLR4 signalling in osteoarthritis—finding targets for candidate DMOADs , 2015, Nature Reviews Rheumatology.

[3]  S. Goldring,et al.  Plasma proteins take their toll on the joint in osteoarthritis , 2012, Arthritis Research & Therapy.

[4]  Y. Konttinen,et al.  Osteoarthritis as an autoinflammatory disease caused by chondrocyte-mediated inflammatory responses. , 2012, Arthritis and rheumatism.

[5]  W. Robinson,et al.  Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4 , 2012, Arthritis Research & Therapy.

[6]  K. Konstantopoulos,et al.  Response of chondrocytes to shear stress: antagonistic effects of the binding partners Toll‐like receptor 4 and caveolin‐1 , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  Ji-Hak Jeong,et al.  Phenolic compounds isolated from Zingiber officinale roots inhibit cell adhesion , 2011 .

[8]  W. B. van den Berg,et al.  Trapped in a vicious loop: Toll-like receptors sustain the spontaneous cytokine production by rheumatoid synovium , 2011, Arthritis research & therapy.

[9]  N. Katunuma.  Structure-based development of specific inhibitors for individual cathepsins and their medical applications , 2011, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[10]  H. Sun.  Mechanical loading, cartilage degradation, and arthritis , 2010, Annals of the New York Academy of Sciences.

[11]  Tessa Therkleson.  Ginger compress therapy for adults with osteoarthritis , 2010, Journal of advanced nursing.

[12]  J. McDougall,et al.  Cathepsin K inhibition reduces CTXII levels and joint pain in the guinea pig model of spontaneous osteoarthritis. , 2010, Osteoarthritis and cartilage.

[13]  Marko Novinec,et al.  Conformational flexibility and allosteric regulation of cathepsin K. , 2010, The Biochemical journal.

[14]  Jeffrey B. Sperry,et al.  Effect of oleocanthal and its derivatives on inflammatory response induced by lipopolysaccharide in a murine chondrocyte cell line. , 2010, Arthritis and rheumatism.

[15]  M. Pichika,et al.  Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. , 2010, Journal of ethnopharmacology.

[16]  Mi-Young Lee,et al.  TBK1-Targeted Suppression of TRIF-Dependent Signaling Pathway of Toll-Like Receptors by 6-Shogaol, an Active Component of Ginger , 2009, Bioscience, biotechnology, and biochemistry.

[17]  T. Spector,et al.  Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford study , 2009, Arthritis and rheumatism.

[18]  L. Klareskog,et al.  Inhibition of cathepsin K reduces bone erosion, cartilage degradation and inflammation evoked by collagen-induced arthritis in mice. , 2009, European journal of pharmacology.

[19]  J. K. Kundu,et al.  Ginger-derived phenolic substances with cancer preventive and therapeutic potential. , 2009, Forum of nutrition.

[20]  D. Loeuille,et al.  Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. , 2009, Arthritis and rheumatism.

[21]  H. Youn,et al.  Inhibition of homodimerization of toll-like receptor 4 by 6-shogaol , 2009, Molecules and cells.

[22]  F. Tsai,et al.  Lipopolysaccharide upregulates uPA, MMP-2 and MMP-9 via ERK1/2 signaling in H9c2 cardiomyoblast cells , 2009, Molecular and Cellular Biochemistry.

[23]  Chi-Tang Ho,et al.  6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages. , 2008, Molecular nutrition & food research.

[24]  S. Abramson.  Nitric oxide in inflammation and pain associated with osteoarthritis , 2008, Arthritis research & therapy.

[25]  M. Crow,et al.  Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? , 2008, Current opinion in rheumatology.

[26]  J. Gómez-Reino,et al.  A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes. , 2008, Osteoarthritis and cartilage.

[27]  S. Zick,et al.  Pharmacokinetics of 6-Gingerol, 8-Gingerol, 10-Gingerol, and 6-Shogaol and Conjugate Metabolites in Healthy Human Subjects , 2008, Cancer Epidemiology Biomarkers & Prevention.

[28]  D. Zukor,et al.  Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. , 2008, The American journal of pathology.

[29]  K. Miyazono,et al.  Cathepsin K-Dependent Toll-Like Receptor 9 Signaling Revealed in Experimental Arthritis , 2008, Science.

[30]  J. Gómez-Reino,et al.  Phosphatidylinositol 3-kinase, MEK-1 and p38 mediate leptin/interferon-gamma synergistic NOS type II induction in chondrocytes. , 2007, Life sciences.

[31]  Jian Huang,et al.  Toll-like receptors in inflammation, infection and cancer. , 2007, International immunopharmacology.

[32]  L. Joosten,et al.  Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. , 2007, Arthritis and rheumatism.

[33]  Ruei-Ming Chen,et al.  Nitric oxide from both exogenous and endogenous sources activates mitochondria‐dependent events and induces insults to human chondrocytes , 2007, Journal of cellular biochemistry.

[34]  E. Vuorio,et al.  Role of cathepsin K in normal joints and in the development of arthritis. , 2007, Current drug targets.

[35]  O. Simon,et al.  6-Shogaol reduced chronic inflammatory response in the knees of rats treated with complete Freund's adjuvant , 2006, BMC pharmacology.

[36]  J. Gómez-Reino,et al.  Partial protection against collagen antibody-induced arthritis in PARP-1 deficient mice , 2005, Arthritis research & therapy.

[37]  Li Yang,et al.  Cytotoxic and apoptotic activities of diarylheptanoids and gingerol-related compounds from the rhizome of Chinese ginger. , 2005, Journal of ethnopharmacology.

[38]  Chwan-Li Shen,et al.  Comparative effects of ginger root (Zingiber officinale Rosc.) on the production of inflammatory mediators in normal and osteoarthrotic sow chondrocytes. , 2005, Journal of medicinal food.

[39]  B. Timmermann,et al.  Commercially processed dry ginger (Zingiber officinale): composition and effects on LPS-stimulated PGE2 production. , 2005, Phytochemistry.

[40]  S. Akira,et al.  Toll-like receptors in innate immunity. , 2004, International immunology.

[41]  W. Bode,et al.  Structural Basis of the Matrix Metalloproteinases and Their Physiological Inhibitors, the Tissue Inhibitors of Metalloproteinases , 2003, Biological chemistry.

[42]  J. Cheong,et al.  Induction of matrix metalloproteinase‐9 (MMP‐9) in lipopolysaccharide‐stimulated primary astrocytes is mediated by extracellular signal‐regulated protein kinase 1/2 (Erk1/2) , 2003, Glia.

[43]  J. Kopeček,et al.  Inhibition of cathepsin K with lysosomotropic macromolecular inhibitors. , 2002, Biochemistry.

[44]  S. Abramson,et al.  Nitric oxide and inflammatory mediators in the perpetuation of osteoarthritis , 2001, Current rheumatology reports.

[45]  J. Moss,et al.  Mitogen-activated Protein Kinases Mediate Activator Protein-1-dependent Human Inducible Nitric-oxide Synthase Promoter Activation* , 2001, The Journal of Biological Chemistry.

[46]  M. Takigawa,et al.  Nitric oxide mediates interleukin-1-induced gene expression of matrix metalloproteinases and basic fibroblast growth factor in cultured rabbit articular chondrocytes. , 1998, Journal of biochemistry.

[47]  T. Schirmeister,et al.  Cysteine Proteases and Their Inhibitors. , 1997, Chemical reviews.

[48]  J. Pelletier,et al.  The increased synthesis of inducible nitric oxide inhibits IL-1ra synthesis by human articular chondrocytes: possible role in osteoarthritic cartilage degradation. , 1996, Osteoarthritis and cartilage.

[49]  G. Solladié,et al.  Total synthesis of natural gingerols, the three active principles of ginger , 1993 .

[50]  K. C. Srivastava,et al.  Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders. , 1992, Medical hypotheses.

[51]  K. C. Srivastava,et al.  Ginger (Zingiber officinale) in migraine headache. , 1990, Journal of ethnopharmacology.

[52]  A. Ishige,et al.  Pharmacological studies on ginger. I. Pharmacological actions of pungent constitutents, (6)-gingerol and (6)-shogaol. , 1984, Journal of pharmacobio-dynamics.

[53]  L. Mathew,et al.  6-Shogaol inhibits monosodium urate crystal-induced inflammation--an in vivo and in vitro study. , 2010, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[54]  L. Joosten,et al.  Growth Factors, Cytokines, Cell Cycle Molecules Local Interleukin-1-Driven Joint Pathology Is Dependent on Toll-Like Receptor 4 Activation , 2009 .