l-Glutathione enhances antioxidant capacity of hyaluronic acid and modulates expression of pro-inflammatory cytokines in human fibroblast-like synoviocytes

K.-C. Yang; Chang Chin Wu; Wei Yu Chen; S. Sumi; Teng Le Huang

doi:10.1002/jbm.a.35729

l-Glutathione enhances antioxidant capacity of hyaluronic acid and modulates expression of pro-inflammatory cytokines in human fibroblast-like synoviocytes

K.-C. Yang, Chang Chin Wu, Wei Yu Chen, S. Sumi, Teng Le Huang

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

Abstract

Intra-articular injection of hyaluronic acid (HA) has been widely accepted for the treatment of osteoarthritis (OA) in early stage. l-Glutathione (GSH), an antioxidant, has an anti-inflammatory effect on protecting cells from reactive oxygen species and reactive nitrogen species (ROS/RNS). In this study, the therapeutic effects of HA (0.1%) supplemented with GSH (0, 5, 10, and 20% in weight ratios to HA) on human fibroblast-like synoviocytes (FLSs) were evaluated. The results showed that cell morphology and glycosaminoglycan production of FLSs were not changed under treatments. However, the addition of HA + 20% GSH significantly decreased cell survival (p <0.001) relative to other groups. Relative to un-stimulated FLSs, interleukin-1 beta (IL-1β) stimulation significantly decreased the total antioxidant capacity (p <0.001) of cells. The antioxidant capacity was restored and the intracellular ROS/RNS was decreased in HA or HA + GSH-treated FLSs. Real-time PCR analysis revealed the mRNA levels of IL-1β, tumor necrosis factor-alpha, and matrix metalloproteinase-3 were down-regulated significantly (all p <0.05) when FLSs cultured in HA or HA + GSH. IL-6 mRNA expressions were down-regulated significantly in HA and HA + 5% GSH groups (both p <0.05) but up-regulated when HA supplemented with 10% and 20% GSH (both p <0.01). In addition, the protein levels of IL-1β were further decreased with significant differences (both p <0.05) in the HA + 10% GSH and HA + 20% GSH groups when compared to FLSs cultured in normal medium. In conclusion, HA supplemented with GSH improves antioxidant capacity and modulates pro-inflammatory cytokines expressions in FLSs. GSH has the potential to augment the effect of viscosupplementation using HA on OA patients. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2071–2079, 2016. © 2016 Wiley Periodicals, Inc.

Original language	English
Pages (from-to)	2071-2079
Number of pages	9
Journal	Journal of Biomedical Materials Research - Part A
Volume	104
Issue number	8
DOIs	https://doi.org/10.1002/jbm.a.35729
Publication status	Published - 2016

Keywords

fibroblast-like synoviocyte
glutathione
hyaluronic acid
osteoarthritis
Antioxidants
Cell culture
Cells
Cytology
Enzyme activity
Fibroblasts
Organic acids
Peptides
Polymerase chain reaction
Tissue
Glutathiones
Intra-articular injection
Matrix-metalloproteinase-3
Pro-inflammatory cytokines
Synoviocytes
Total antioxidant capacity
Tumor necrosis factor alpha
Hyaluronic acid

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10.1002/jbm.a.35729

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Cite this

@article{abfe41c8f8474f0997c365db55feaebe,

title = "l-Glutathione enhances antioxidant capacity of hyaluronic acid and modulates expression of pro-inflammatory cytokines in human fibroblast-like synoviocytes",

abstract = "Intra-articular injection of hyaluronic acid (HA) has been widely accepted for the treatment of osteoarthritis (OA) in early stage. l-Glutathione (GSH), an antioxidant, has an anti-inflammatory effect on protecting cells from reactive oxygen species and reactive nitrogen species (ROS/RNS). In this study, the therapeutic effects of HA (0.1%) supplemented with GSH (0, 5, 10, and 20% in weight ratios to HA) on human fibroblast-like synoviocytes (FLSs) were evaluated. The results showed that cell morphology and glycosaminoglycan production of FLSs were not changed under treatments. However, the addition of HA + 20% GSH significantly decreased cell survival (p <0.001) relative to other groups. Relative to un-stimulated FLSs, interleukin-1 beta (IL-1β) stimulation significantly decreased the total antioxidant capacity (p <0.001) of cells. The antioxidant capacity was restored and the intracellular ROS/RNS was decreased in HA or HA + GSH-treated FLSs. Real-time PCR analysis revealed the mRNA levels of IL-1β, tumor necrosis factor-alpha, and matrix metalloproteinase-3 were down-regulated significantly (all p <0.05) when FLSs cultured in HA or HA + GSH. IL-6 mRNA expressions were down-regulated significantly in HA and HA + 5% GSH groups (both p <0.05) but up-regulated when HA supplemented with 10% and 20% GSH (both p <0.01). In addition, the protein levels of IL-1β were further decreased with significant differences (both p <0.05) in the HA + 10% GSH and HA + 20% GSH groups when compared to FLSs cultured in normal medium. In conclusion, HA supplemented with GSH improves antioxidant capacity and modulates pro-inflammatory cytokines expressions in FLSs. GSH has the potential to augment the effect of viscosupplementation using HA on OA patients. {\textcopyright} 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2071–2079, 2016. {\textcopyright} 2016 Wiley Periodicals, Inc.",

keywords = "fibroblast-like synoviocyte, glutathione, hyaluronic acid, osteoarthritis, Antioxidants, Cell culture, Cells, Cytology, Enzyme activity, Fibroblasts, Organic acids, Peptides, Polymerase chain reaction, Tissue, Glutathiones, Intra-articular injection, Matrix-metalloproteinase-3, Pro-inflammatory cytokines, Synoviocytes, Total antioxidant capacity, Tumor necrosis factor alpha, Hyaluronic acid",

author = "K.-C. Yang and Wu, {Chang Chin} and Chen, {Wei Yu} and S. Sumi and Huang, {Teng Le}",

note = "Export Date: 24 August 2016 CODEN: JBMRC 通訊地址: Huang, T.-L.; Department of Sports Medicine, College of Health Care, China Medical UniversityTaiwan; 電子郵件： [email protected] 參考文獻: Balazs, E.A., Denlinger, J., Viscosupplementation: A new concept in the treatment of osteoarthritis (1993) J Rheumatol, 20, pp. 3-9; Arrich, J., Piribauer, F., Mad, P., Schmid, D., Klaushofer, K., M{\"u}llner, M., Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis (2005) CMAJ, 172, pp. 1039-1043; Printz, J.O., Lee, J., Knesek, M., Urquhart, A.G., Conflict of interest in the assessment of hyaluronic acid injections for osteoarthritis of the knee: An updated systematic review (2013) J Arthroplasty, 2814, p. 33. , MD; Fam, H., Bryant, J.T., Kontopoulou, M., Rheological properties of synovial fluids (2007) Biorheology, 44, pp. 59-74; Akmal, M., Singh, A., Anand, A., Kesani, A., Aslam, N., Goodship, A., Bentley, G., The effects of hyaluronic acid on articular chondrocytes (2005) J Bone Joint Surg Br, 87, pp. 1143-1149; Lee, P.B., Kim, Y.C., Lim, Y.J., Lee, C.J., Sim, W.S., Ha, C.W., Bin, S.I., Lee, S.C., Comparison between high and low molecular weight hyaluronates in knee osteoarthritis patients: open-label, randomized, multicentre clinical trial (2006) J Int Med Res, 34, pp. 77-87; Kirchner, M., Marshall, D., A double-blind randomized controlled trial comparing alternate forms of high molecular weight hyaluronan for the treatment of osteoarthritis of the knee (2006) Osteoarthritis Cartilage, 14, pp. 154-162; Calmbach, W.L., Hutchens, M., Evaluation of patients presenting with knee pain: Part II. Differential diagnosis (2003) Am Fam Phys, 68, pp. 917-922; Zwerina, J., Hayer, S., Tohidast-Akrad, M., Bergmeister, H., Redlich, K., Feige, U., Dunstan, C., Schett, G., Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: Effects on synovial inflammation, bone erosion, and cartilage destruction (2004) Arthritis Rheum, 5020, p. 290; Kim, J., Xu, M., Xo, R., Mates, A., Wilson, G.L., Pearsall, A.W., 4th, Grishko, V., Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes (2010) Osteoarthritis Cartilage, 18, pp. 424-432; Henrotin, Y., Kurz, B., Aigner, T., Oxygen and reactive oxygen species in cartilage degradation: friends or foes? (2005) Osteoarthritis Cartilage, 13, pp. 643-654; Ostalowska, A., Birkner, E., Wiecha, M., Kasperczyk, S., Kasperczyk, A., Kapolka, D., Zon-Giebel, A., Lipid peroxidation and antioxidant enzymes in synovial fluid of patients with primary and secondary osteoarthritis of the knee joint (2006) Osteoarthritis Cartilage, 14, pp. 139-145; Bubici, C., Papa, S., Dean, K., Franzoso, G., Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance (2006) Oncogene, 25, pp. 6731-6748; Hiramitsu, T., Yasuda, T., Ito, H., Shimizu, M., Julovi, S.M., Kakinuma, T., Akiyoshi, M., Nakamura, T., Intercellular adhesion molecule-1 mediates the inhibitory effects of hyaluronan on interleukin-1beta-induced matrix metalloproteinase production in rheumatoid synovial fibroblasts via down-regulation of NF-kappaB and p38. 26 (2006) Rheumatology (Oxford), 45, pp. 824-832; Westacott, C.I., Barakat, A.F., Wood, L., Perry, M.J., Neison, P., Bisbinas, I., Tumor necrosis factor alpha can contribute to focal loss of cartilage in osteoarthritis (2000) Osteoarthritis Cartilage, 8, pp. 213-221; Regan, E.A., Bowler, R.P., Crapo, J.D., Joint fluid antioxidants are decreased in osteoarthritic joints compared to joints with macroscopically intact cartilage and subacute injury (2008) Osteoarthritis Cartilage, 16, pp. 515-521; Habuchi, O., Miyachi, T., Kaigawa, S., Nakashima, S., Fujiwara, C., Hisada, M., Effects of glutathione depletion on the synthesis of proteoglycan and collagen in cultured chondrocytes (1991) Biochim Biophys Acta, 1093, pp. 153-161; Ostalowska, A., Birkner, E., Wiecha, M., Kasperczyk, S., Kasperczyk, A., Kapolka, D., Zon-Giebel, A., Lipid peroxidation and antioxidant enzymes in synovial fluid of patients with primary and secondary osteoarthritis of the knee joint Osteoarthritis Cartilage, 14, pp. 139-145; Afonso, V., Champy, R., Mitrovic, D., Collin, P., Lomri, A., Reactive oxygen species and superoxide dismutases: Role in joint diseases (2007) Joint Bone Spine, 32, pp. 324-329; Ohata, J., Zvaifler, N.J., Nishio, M., Boyle, D.L., Kalled, S.L., Carson, D.A., Kipps, T.J., Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines (2005) J Immunol, 174, pp. 864-870; Bartok, B., Firestein, G.S., Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis (2010) Immunol Rev, 233, pp. 233-255; Carlo, M.D., Jr., Loeser, R.F., Increased oxidative stress with aging reduces chondrocyte survival: correlation with intracellular glutathione levels (2003) Arthritis Rheum, 48, pp. 3419-3430; Greenberg, D.D., Stoker, A., Kane, S., Cockrell, M., Cook, J.L., Biochemical effects of two different hyaluronic acid products in a co-culture model of osteoarthritis (2006) Osteoarthritis Cartilage, 14, pp. 814-822; Steenvoorden, M.M., Huizinga, T.W., Verzijl, N., Bank, R.A., Ronday, H.K., Luning, H.A., Lafeber, F.P., DeGroot, J., Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes (2006) Arthritis Rheum, 54, pp. 253-263; Takahashi, K., Hashimoto, S., Kubo, T., Hirasawa, Y., Lotz, M., Amiel, D., Hyaluronan suppressed nitric oxide production in the meniscus and synovium of rabbit osteoarthritis model (2001) J Orthop Res, 19, pp. 500-503; Gregg, A.J., Fortier, L.A., Mohammed, H.O., Mayr, K.G., Miller, B.J., Haupt, J.L., Assessment of the catabolic effects of interleukin-1beta on proteoglycan metabolism in equine cartilage cocultured with synoviocytes (2006) Am J Vet Res, 67, pp. 957-962; Lin, W.Y., Sadhasivam, S., Lin, F.H., The dose dependent effects of betulin on porcine chondrocytes (2009) Process Biochem, 44, pp. 678-684; Chen, P.Y., Hsu, C.C., Yang, K.C., Wu, C.C., Wang, C.L., The effects of negative pressure treatment on the extracellular matrix gene expression and protein production of fibroblasts (2015) Process Biochem, 50, pp. 1662-1668; Yang, S.H., Lin, C.C., Hu, M.H., Shih, T.T., Sun, Y.H., Lin, F.H., Influence of age-related degeneration on regenerative potential of human nucleus pulposus cells (2010) J Orthop Res, 28, pp. 379-383; Chen, M.P., Yang, S.H., Chou, C.H., Yang, K.C., Wu, C.C., Cheng, Y.H., Lin, F.H., The chondroprotective effects of ferulic acid on hydrogen peroxide-stimulated chondrocytes: Inhibition of hydrogen peroxide-induced pro-inflammatory cytokines and metalloproteinase gene expression at the mRNA level (2010) Inflamm Res, 59, pp. 587-595; Yang, K.C., Chen, H.T., Wu, C.C., Lian, Y.J., Chen, L.L., Sumi, S., Huang, T.L.L., Glutamine regulates the expression of matrix proteins, pro-inflammatory cytokines and catabolic enzymes in IL-1β-stimulated human chondrocytes (2016) Process Biochem, 51, pp. 414-421; Mathy-Hartert, M., Hogge, L., Sanchez, C., Deby-Dupont, G., Crielaard, J.M., Henrotin, Y., Interleukin-1beta and interleukin-6 disturb the antioxidant enzyme system in bovine chondrocytes: A possible explanation for oxidative stress generation (2008) Osteoarthritis Cartilage, 1649, p. 763; Wang, C.T., Lin, Y.T., Chiang, B.L., Lin, Y.H., Hou, S.M., High molecular weight hyaluronic acid down-regulates the gene expression of osteoarthritis-associated cytokines and enzymes in fibroblast-like synoviocytes from patients with early osteoarthritis (2006) Osteoarthritis Cartilage, 50, pp. 1237-1247; Kataoka, Y., Ariyoshi, W., Okinaga, T., Kaneuji, T., Mitsugi, S., Takahashi, T., Nishihara, T., Mechanisms involved in suppression of ADAMTS4 expression in synoviocytes by high molecular weight hyaluronic acid (2013) Biochem Biophys Res Commun, 432, pp. 580-585; Sakkas, L.I., Scanzello, C., Johanson, N., Burkholder, J., Mitra, A., Salgame, P., Katsetos, C.D., Platsoucas, C.D., T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis (1998) Clin Diagn Lab Immunol, 5, pp. 430-437; Moos, V., Fickert, S., Muller, B., Weber, U., Sieper, J., Immunohistological analysis of cytokine expression in human osteoarthritic and healthy cartilage (1999) J Rheumatol, 26, pp. 870-879; Martel-Pelletier, J., Pathophysiology of osteoarthritis (2004) Osteoarthritis Cartilage, 12, pp. S31-S33; Chakraborti, S., Mandal, M., Das, S., Mandal, A., Chakraborti, T., Regulation of matrix metalloproteinases: An overview (2003) Mol Cell Biochem, 253, pp. 269-285; Stannus, O., Jones, G., Cicuttini, F., Parameswaran, V., Quinn, S., Burgess, J., Ding, C., Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults (2010) Osteoarthritis Cartilage, 18, pp. 1441-1447; Doss, F., Menard, J., Hauschild, M., Kreutzer, H.J., Mittlmeier, T., M{\"u}ller-Steinhardt, M., M{\"u}ller, B., Elevated IL-6 levels in the synovial fluid of osteoarthritis patients stem from plasma cells (2007) Scand J Rheumatol, 36, pp. 136-139; van de Loo, F.A., Kuiper, S., van Enckevort, F.H., Arntz, O.J., van den Berg, W.B., Interleukin-6 reduces cartilage destruction during experimental arthritis. A study in interleukin-6-deficient mice (1997) Am J Pathol, 151, pp. 177-191; de Hooge, A.S., van de Loo, F.A., Bennink, M.B., Arntz, O.J., de Hooge, P., van den Berg, W.B., Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging (2005) Osteoarthritis Cartilage, 13, pp. 66-73; Silacci, P., Dayer, J.M., Desgeorges, A., Peter, R., Manueddu, C., Guerne, P.A., Interleukin (IL)−6 and its soluble receptor induce TIMP-1 expression in synoviocytes and chondrocytes, and block IL-1-induced collagenolytic activity (1998) J Biol Chem, 273, p. 13625",

year = "2016",

doi = "10.1002/jbm.a.35729",

language = "English",

volume = "104",

pages = "2071--2079",

journal = "Journal of Biomedical Materials Research - Part A",

issn = "1549-3296",

publisher = "John Wiley and Sons Inc.",

number = "8",

}

TY - JOUR

T1 - l-Glutathione enhances antioxidant capacity of hyaluronic acid and modulates expression of pro-inflammatory cytokines in human fibroblast-like synoviocytes

AU - Yang, K.-C.

AU - Wu, Chang Chin

AU - Chen, Wei Yu

AU - Sumi, S.

AU - Huang, Teng Le

N1 - Export Date: 24 August 2016 CODEN: JBMRC 通訊地址: Huang, T.-L.; Department of Sports Medicine, College of Health Care, China Medical UniversityTaiwan; 電子郵件： [email protected] 參考文獻: Balazs, E.A., Denlinger, J., Viscosupplementation: A new concept in the treatment of osteoarthritis (1993) J Rheumatol, 20, pp. 3-9; Arrich, J., Piribauer, F., Mad, P., Schmid, D., Klaushofer, K., Müllner, M., Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis (2005) CMAJ, 172, pp. 1039-1043; Printz, J.O., Lee, J., Knesek, M., Urquhart, A.G., Conflict of interest in the assessment of hyaluronic acid injections for osteoarthritis of the knee: An updated systematic review (2013) J Arthroplasty, 2814, p. 33. , MD; Fam, H., Bryant, J.T., Kontopoulou, M., Rheological properties of synovial fluids (2007) Biorheology, 44, pp. 59-74; Akmal, M., Singh, A., Anand, A., Kesani, A., Aslam, N., Goodship, A., Bentley, G., The effects of hyaluronic acid on articular chondrocytes (2005) J Bone Joint Surg Br, 87, pp. 1143-1149; Lee, P.B., Kim, Y.C., Lim, Y.J., Lee, C.J., Sim, W.S., Ha, C.W., Bin, S.I., Lee, S.C., Comparison between high and low molecular weight hyaluronates in knee osteoarthritis patients: open-label, randomized, multicentre clinical trial (2006) J Int Med Res, 34, pp. 77-87; Kirchner, M., Marshall, D., A double-blind randomized controlled trial comparing alternate forms of high molecular weight hyaluronan for the treatment of osteoarthritis of the knee (2006) Osteoarthritis Cartilage, 14, pp. 154-162; Calmbach, W.L., Hutchens, M., Evaluation of patients presenting with knee pain: Part II. Differential diagnosis (2003) Am Fam Phys, 68, pp. 917-922; Zwerina, J., Hayer, S., Tohidast-Akrad, M., Bergmeister, H., Redlich, K., Feige, U., Dunstan, C., Schett, G., Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: Effects on synovial inflammation, bone erosion, and cartilage destruction (2004) Arthritis Rheum, 5020, p. 290; Kim, J., Xu, M., Xo, R., Mates, A., Wilson, G.L., Pearsall, A.W., 4th, Grishko, V., Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes (2010) Osteoarthritis Cartilage, 18, pp. 424-432; Henrotin, Y., Kurz, B., Aigner, T., Oxygen and reactive oxygen species in cartilage degradation: friends or foes? (2005) Osteoarthritis Cartilage, 13, pp. 643-654; Ostalowska, A., Birkner, E., Wiecha, M., Kasperczyk, S., Kasperczyk, A., Kapolka, D., Zon-Giebel, A., Lipid peroxidation and antioxidant enzymes in synovial fluid of patients with primary and secondary osteoarthritis of the knee joint (2006) Osteoarthritis Cartilage, 14, pp. 139-145; Bubici, C., Papa, S., Dean, K., Franzoso, G., Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance (2006) Oncogene, 25, pp. 6731-6748; Hiramitsu, T., Yasuda, T., Ito, H., Shimizu, M., Julovi, S.M., Kakinuma, T., Akiyoshi, M., Nakamura, T., Intercellular adhesion molecule-1 mediates the inhibitory effects of hyaluronan on interleukin-1beta-induced matrix metalloproteinase production in rheumatoid synovial fibroblasts via down-regulation of NF-kappaB and p38. 26 (2006) Rheumatology (Oxford), 45, pp. 824-832; Westacott, C.I., Barakat, A.F., Wood, L., Perry, M.J., Neison, P., Bisbinas, I., Tumor necrosis factor alpha can contribute to focal loss of cartilage in osteoarthritis (2000) Osteoarthritis Cartilage, 8, pp. 213-221; Regan, E.A., Bowler, R.P., Crapo, J.D., Joint fluid antioxidants are decreased in osteoarthritic joints compared to joints with macroscopically intact cartilage and subacute injury (2008) Osteoarthritis Cartilage, 16, pp. 515-521; Habuchi, O., Miyachi, T., Kaigawa, S., Nakashima, S., Fujiwara, C., Hisada, M., Effects of glutathione depletion on the synthesis of proteoglycan and collagen in cultured chondrocytes (1991) Biochim Biophys Acta, 1093, pp. 153-161; Ostalowska, A., Birkner, E., Wiecha, M., Kasperczyk, S., Kasperczyk, A., Kapolka, D., Zon-Giebel, A., Lipid peroxidation and antioxidant enzymes in synovial fluid of patients with primary and secondary osteoarthritis of the knee joint Osteoarthritis Cartilage, 14, pp. 139-145; Afonso, V., Champy, R., Mitrovic, D., Collin, P., Lomri, A., Reactive oxygen species and superoxide dismutases: Role in joint diseases (2007) Joint Bone Spine, 32, pp. 324-329; Ohata, J., Zvaifler, N.J., Nishio, M., Boyle, D.L., Kalled, S.L., Carson, D.A., Kipps, T.J., Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines (2005) J Immunol, 174, pp. 864-870; Bartok, B., Firestein, G.S., Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis (2010) Immunol Rev, 233, pp. 233-255; Carlo, M.D., Jr., Loeser, R.F., Increased oxidative stress with aging reduces chondrocyte survival: correlation with intracellular glutathione levels (2003) Arthritis Rheum, 48, pp. 3419-3430; Greenberg, D.D., Stoker, A., Kane, S., Cockrell, M., Cook, J.L., Biochemical effects of two different hyaluronic acid products in a co-culture model of osteoarthritis (2006) Osteoarthritis Cartilage, 14, pp. 814-822; Steenvoorden, M.M., Huizinga, T.W., Verzijl, N., Bank, R.A., Ronday, H.K., Luning, H.A., Lafeber, F.P., DeGroot, J., Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes (2006) Arthritis Rheum, 54, pp. 253-263; Takahashi, K., Hashimoto, S., Kubo, T., Hirasawa, Y., Lotz, M., Amiel, D., Hyaluronan suppressed nitric oxide production in the meniscus and synovium of rabbit osteoarthritis model (2001) J Orthop Res, 19, pp. 500-503; Gregg, A.J., Fortier, L.A., Mohammed, H.O., Mayr, K.G., Miller, B.J., Haupt, J.L., Assessment of the catabolic effects of interleukin-1beta on proteoglycan metabolism in equine cartilage cocultured with synoviocytes (2006) Am J Vet Res, 67, pp. 957-962; Lin, W.Y., Sadhasivam, S., Lin, F.H., The dose dependent effects of betulin on porcine chondrocytes (2009) Process Biochem, 44, pp. 678-684; Chen, P.Y., Hsu, C.C., Yang, K.C., Wu, C.C., Wang, C.L., The effects of negative pressure treatment on the extracellular matrix gene expression and protein production of fibroblasts (2015) Process Biochem, 50, pp. 1662-1668; Yang, S.H., Lin, C.C., Hu, M.H., Shih, T.T., Sun, Y.H., Lin, F.H., Influence of age-related degeneration on regenerative potential of human nucleus pulposus cells (2010) J Orthop Res, 28, pp. 379-383; Chen, M.P., Yang, S.H., Chou, C.H., Yang, K.C., Wu, C.C., Cheng, Y.H., Lin, F.H., The chondroprotective effects of ferulic acid on hydrogen peroxide-stimulated chondrocytes: Inhibition of hydrogen peroxide-induced pro-inflammatory cytokines and metalloproteinase gene expression at the mRNA level (2010) Inflamm Res, 59, pp. 587-595; Yang, K.C., Chen, H.T., Wu, C.C., Lian, Y.J., Chen, L.L., Sumi, S., Huang, T.L.L., Glutamine regulates the expression of matrix proteins, pro-inflammatory cytokines and catabolic enzymes in IL-1β-stimulated human chondrocytes (2016) Process Biochem, 51, pp. 414-421; Mathy-Hartert, M., Hogge, L., Sanchez, C., Deby-Dupont, G., Crielaard, J.M., Henrotin, Y., Interleukin-1beta and interleukin-6 disturb the antioxidant enzyme system in bovine chondrocytes: A possible explanation for oxidative stress generation (2008) Osteoarthritis Cartilage, 1649, p. 763; Wang, C.T., Lin, Y.T., Chiang, B.L., Lin, Y.H., Hou, S.M., High molecular weight hyaluronic acid down-regulates the gene expression of osteoarthritis-associated cytokines and enzymes in fibroblast-like synoviocytes from patients with early osteoarthritis (2006) Osteoarthritis Cartilage, 50, pp. 1237-1247; Kataoka, Y., Ariyoshi, W., Okinaga, T., Kaneuji, T., Mitsugi, S., Takahashi, T., Nishihara, T., Mechanisms involved in suppression of ADAMTS4 expression in synoviocytes by high molecular weight hyaluronic acid (2013) Biochem Biophys Res Commun, 432, pp. 580-585; Sakkas, L.I., Scanzello, C., Johanson, N., Burkholder, J., Mitra, A., Salgame, P., Katsetos, C.D., Platsoucas, C.D., T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis (1998) Clin Diagn Lab Immunol, 5, pp. 430-437; Moos, V., Fickert, S., Muller, B., Weber, U., Sieper, J., Immunohistological analysis of cytokine expression in human osteoarthritic and healthy cartilage (1999) J Rheumatol, 26, pp. 870-879; Martel-Pelletier, J., Pathophysiology of osteoarthritis (2004) Osteoarthritis Cartilage, 12, pp. S31-S33; Chakraborti, S., Mandal, M., Das, S., Mandal, A., Chakraborti, T., Regulation of matrix metalloproteinases: An overview (2003) Mol Cell Biochem, 253, pp. 269-285; Stannus, O., Jones, G., Cicuttini, F., Parameswaran, V., Quinn, S., Burgess, J., Ding, C., Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults (2010) Osteoarthritis Cartilage, 18, pp. 1441-1447; Doss, F., Menard, J., Hauschild, M., Kreutzer, H.J., Mittlmeier, T., Müller-Steinhardt, M., Müller, B., Elevated IL-6 levels in the synovial fluid of osteoarthritis patients stem from plasma cells (2007) Scand J Rheumatol, 36, pp. 136-139; van de Loo, F.A., Kuiper, S., van Enckevort, F.H., Arntz, O.J., van den Berg, W.B., Interleukin-6 reduces cartilage destruction during experimental arthritis. A study in interleukin-6-deficient mice (1997) Am J Pathol, 151, pp. 177-191; de Hooge, A.S., van de Loo, F.A., Bennink, M.B., Arntz, O.J., de Hooge, P., van den Berg, W.B., Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging (2005) Osteoarthritis Cartilage, 13, pp. 66-73; Silacci, P., Dayer, J.M., Desgeorges, A., Peter, R., Manueddu, C., Guerne, P.A., Interleukin (IL)−6 and its soluble receptor induce TIMP-1 expression in synoviocytes and chondrocytes, and block IL-1-induced collagenolytic activity (1998) J Biol Chem, 273, p. 13625

PY - 2016

Y1 - 2016

N2 - Intra-articular injection of hyaluronic acid (HA) has been widely accepted for the treatment of osteoarthritis (OA) in early stage. l-Glutathione (GSH), an antioxidant, has an anti-inflammatory effect on protecting cells from reactive oxygen species and reactive nitrogen species (ROS/RNS). In this study, the therapeutic effects of HA (0.1%) supplemented with GSH (0, 5, 10, and 20% in weight ratios to HA) on human fibroblast-like synoviocytes (FLSs) were evaluated. The results showed that cell morphology and glycosaminoglycan production of FLSs were not changed under treatments. However, the addition of HA + 20% GSH significantly decreased cell survival (p <0.001) relative to other groups. Relative to un-stimulated FLSs, interleukin-1 beta (IL-1β) stimulation significantly decreased the total antioxidant capacity (p <0.001) of cells. The antioxidant capacity was restored and the intracellular ROS/RNS was decreased in HA or HA + GSH-treated FLSs. Real-time PCR analysis revealed the mRNA levels of IL-1β, tumor necrosis factor-alpha, and matrix metalloproteinase-3 were down-regulated significantly (all p <0.05) when FLSs cultured in HA or HA + GSH. IL-6 mRNA expressions were down-regulated significantly in HA and HA + 5% GSH groups (both p <0.05) but up-regulated when HA supplemented with 10% and 20% GSH (both p <0.01). In addition, the protein levels of IL-1β were further decreased with significant differences (both p <0.05) in the HA + 10% GSH and HA + 20% GSH groups when compared to FLSs cultured in normal medium. In conclusion, HA supplemented with GSH improves antioxidant capacity and modulates pro-inflammatory cytokines expressions in FLSs. GSH has the potential to augment the effect of viscosupplementation using HA on OA patients. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2071–2079, 2016. © 2016 Wiley Periodicals, Inc.

AB - Intra-articular injection of hyaluronic acid (HA) has been widely accepted for the treatment of osteoarthritis (OA) in early stage. l-Glutathione (GSH), an antioxidant, has an anti-inflammatory effect on protecting cells from reactive oxygen species and reactive nitrogen species (ROS/RNS). In this study, the therapeutic effects of HA (0.1%) supplemented with GSH (0, 5, 10, and 20% in weight ratios to HA) on human fibroblast-like synoviocytes (FLSs) were evaluated. The results showed that cell morphology and glycosaminoglycan production of FLSs were not changed under treatments. However, the addition of HA + 20% GSH significantly decreased cell survival (p <0.001) relative to other groups. Relative to un-stimulated FLSs, interleukin-1 beta (IL-1β) stimulation significantly decreased the total antioxidant capacity (p <0.001) of cells. The antioxidant capacity was restored and the intracellular ROS/RNS was decreased in HA or HA + GSH-treated FLSs. Real-time PCR analysis revealed the mRNA levels of IL-1β, tumor necrosis factor-alpha, and matrix metalloproteinase-3 were down-regulated significantly (all p <0.05) when FLSs cultured in HA or HA + GSH. IL-6 mRNA expressions were down-regulated significantly in HA and HA + 5% GSH groups (both p <0.05) but up-regulated when HA supplemented with 10% and 20% GSH (both p <0.01). In addition, the protein levels of IL-1β were further decreased with significant differences (both p <0.05) in the HA + 10% GSH and HA + 20% GSH groups when compared to FLSs cultured in normal medium. In conclusion, HA supplemented with GSH improves antioxidant capacity and modulates pro-inflammatory cytokines expressions in FLSs. GSH has the potential to augment the effect of viscosupplementation using HA on OA patients. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2071–2079, 2016. © 2016 Wiley Periodicals, Inc.

KW - fibroblast-like synoviocyte

KW - glutathione

KW - hyaluronic acid

KW - osteoarthritis

KW - Antioxidants

KW - Cell culture

KW - Cells

KW - Cytology

KW - Enzyme activity

KW - Fibroblasts

KW - Organic acids

KW - Peptides

KW - Polymerase chain reaction

KW - Tissue

KW - Glutathiones

KW - Intra-articular injection

KW - Matrix-metalloproteinase-3

KW - Pro-inflammatory cytokines

KW - Synoviocytes

KW - Total antioxidant capacity

KW - Tumor necrosis factor alpha

KW - Hyaluronic acid

U2 - 10.1002/jbm.a.35729

DO - 10.1002/jbm.a.35729

M3 - Article

SN - 1549-3296

VL - 104

SP - 2071

EP - 2079

JO - Journal of Biomedical Materials Research - Part A

JF - Journal of Biomedical Materials Research - Part A

IS - 8

ER -

l-Glutathione enhances antioxidant capacity of hyaluronic acid and modulates expression of pro-inflammatory cytokines in human fibroblast-like synoviocytes

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