硫酸氨基葡萄糖对白细胞介素1β诱导人骨关节炎软骨细胞合成前列腺素E_2和一氧化氮的影响
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摘要
目的 研究硫酸氨基葡萄糖对白细胞介素1β(Interleukin 1β，IL-1β)诱导体外培养的人骨关节炎软骨细胞合成前列腺素E_2(prostaglandin E_2，PGE_2)和一氧化氮(nitric oxide，NO)的影响及其作用机制。
方法 取10例骨关节炎患者接受全膝关节置换术的的股骨髁和胫骨平台软骨标本，酶消化法获取软骨细胞进行体外培养。在原代或第二代的人骨关节炎软骨细胞(human osteoarthritic chondrocytes，HOC)培养液中加入IL-1β(5ng／ml)和不同浓度的硫酸氨基葡萄糖(0.2mmol／1，2mmol／1，20mmol／1)作用24小时，首先应用ELISA法检测细胞上清中的PGE_2，白介素1受体抗体(Interleukin-1 receptor antagonist，IL-1Ra)，硝酸还原酶法检测细胞上清中的NO的含量，然后应用RT-PCR法和Western蛋白印迹法分别检测HOC中环氧化酶2(cyclooxygenase 2，COX-2)、诱导型一氧化氮合酶(inductive nitric
oxide synthetase，iNOS)mRNA和蛋白的表达，应用RT-PCR法检测HOC中Ⅱ型白介素1受体(Interleukin-1 receptor type Ⅱ，IL-1RⅡ)的mRNA表达。
结果 IL-1β刺激后HOC合成PGE_2和NO增加(P＜0.01)，表达COX-2、iNOS mRNA和蛋白上调(P＜0.01)，表达IL-1Ra上调(P＜0.01)，表达IL-1RⅡ的mRNA下调(P＜0.01)。0.2mmol／l，2mmol／和20mmol／l硫酸氨基葡萄糖以浓度依赖的方式抑制IL-1β诱导HOC合成PGE_2(P＜0.01)，抑制IL-1β诱导HOC表达COX-2 mRNA和蛋白上调(P＜0.01)。2mmol／和20mmol／l硫酸氨基葡萄糖以浓度依赖的方式抑制IL-1β诱导HOC合成NO(P＜0.05)，抑制IL-1β诱导HOC表达iNOS mRNA和蛋白的上调(P＜0.05)，抑制IL-1β诱导HOC表达IL-1RⅡ的mRNA的下调(P＜0.05)。但硫酸氨基葡萄糖对软骨细胞合成IL-1Ra无影响(P＞
Osteoarthritis is the most common joint disorder and has an immense socioeconomic impact. Many studies have demonstrated that cartilage from patients with OA is characterized by accelerated turnover of the cartilage matrix components and inadequate repair.
Glucosamine sulfate (GS) represents a new generation of drug and were originally suggested to promote the repair of damaged cartilage. Available experimental data indicate that GS may possess both chondroprotective and anti-inflammatory effects. The chondroprotective action of GS manifests as acceleration of glycosaminoglycan synthesis in cultured chondrocytes and cartilage tissue. Although anti-exudative and anti-inflammatory activities of GS were lower as compared with those of acetylsalicylic acid or indomethacin, glucosamine was found to be synergistic in its anti-exudative activity with indomethacin, piroxicam, and diclofenac in a mouse model of aseptic inflammation. The modulating effect of glucosamine on human chondrocyte response toward the stimulation with IL-1, describing a novel mechanism of Glucosamine-mediated anti-inflammatory activity. Recent research suggest that the anti-inflammatory effects of glucosamine sulfate could be due to modulation of inflammatory genes expression, including cyclooxygenase 2(COX-2) and inductive nitric oxide synthase (iNOS), but the conclusions drawn from different methods and different authors seem to be controversial.
Another possible mechanism of the anti-inflammatory effects could be that glucosamine sulfate modulates the binding of IL-1 to its receptor via a possible increase in IL-1 receptor type Ⅱ(IL-1RⅡ), which is a decoy receptor. Its interaction with IL-1 is unable to generate signaling.
Based on these theorys, the following experiment was desgined. Objective The current study aims at presenting experimental evidence that GS could modulate IL-1β induced activation of human osteoarthritic
方法 取10例骨关节炎患者接受全膝关节置换术的的股骨髁和胫骨平台软骨标本，酶消化法获取软骨细胞进行体外培养。在原代或第二代的人骨关节炎软骨细胞(human osteoarthritic chondrocytes，HOC)培养液中加入IL-1β(5ng／ml)和不同浓度的硫酸氨基葡萄糖(0.2mmol／1，2mmol／1，20mmol／1)作用24小时，首先应用ELISA法检测细胞上清中的PGE_2，白介素1受体抗体(Interleukin-1 receptor antagonist，IL-1Ra)，硝酸还原酶法检测细胞上清中的NO的含量，然后应用RT-PCR法和Western蛋白印迹法分别检测HOC中环氧化酶2(cyclooxygenase 2，COX-2)、诱导型一氧化氮合酶(inductive nitric
oxide synthetase，iNOS)mRNA和蛋白的表达，应用RT-PCR法检测HOC中Ⅱ型白介素1受体(Interleukin-1 receptor type Ⅱ，IL-1RⅡ)的mRNA表达。
结果 IL-1β刺激后HOC合成PGE_2和NO增加(P＜0.01)，表达COX-2、iNOS mRNA和蛋白上调(P＜0.01)，表达IL-1Ra上调(P＜0.01)，表达IL-1RⅡ的mRNA下调(P＜0.01)。0.2mmol／l，2mmol／和20mmol／l硫酸氨基葡萄糖以浓度依赖的方式抑制IL-1β诱导HOC合成PGE_2(P＜0.01)，抑制IL-1β诱导HOC表达COX-2 mRNA和蛋白上调(P＜0.01)。2mmol／和20mmol／l硫酸氨基葡萄糖以浓度依赖的方式抑制IL-1β诱导HOC合成NO(P＜0.05)，抑制IL-1β诱导HOC表达iNOS mRNA和蛋白的上调(P＜0.05)，抑制IL-1β诱导HOC表达IL-1RⅡ的mRNA的下调(P＜0.05)。但硫酸氨基葡萄糖对软骨细胞合成IL-1Ra无影响(P＞
Osteoarthritis is the most common joint disorder and has an immense socioeconomic impact. Many studies have demonstrated that cartilage from patients with OA is characterized by accelerated turnover of the cartilage matrix components and inadequate repair.
Glucosamine sulfate (GS) represents a new generation of drug and were originally suggested to promote the repair of damaged cartilage. Available experimental data indicate that GS may possess both chondroprotective and anti-inflammatory effects. The chondroprotective action of GS manifests as acceleration of glycosaminoglycan synthesis in cultured chondrocytes and cartilage tissue. Although anti-exudative and anti-inflammatory activities of GS were lower as compared with those of acetylsalicylic acid or indomethacin, glucosamine was found to be synergistic in its anti-exudative activity with indomethacin, piroxicam, and diclofenac in a mouse model of aseptic inflammation. The modulating effect of glucosamine on human chondrocyte response toward the stimulation with IL-1, describing a novel mechanism of Glucosamine-mediated anti-inflammatory activity. Recent research suggest that the anti-inflammatory effects of glucosamine sulfate could be due to modulation of inflammatory genes expression, including cyclooxygenase 2(COX-2) and inductive nitric oxide synthase (iNOS), but the conclusions drawn from different methods and different authors seem to be controversial.
Another possible mechanism of the anti-inflammatory effects could be that glucosamine sulfate modulates the binding of IL-1 to its receptor via a possible increase in IL-1 receptor type Ⅱ(IL-1RⅡ), which is a decoy receptor. Its interaction with IL-1 is unable to generate signaling.
Based on these theorys, the following experiment was desgined. Objective The current study aims at presenting experimental evidence that GS could modulate IL-1β induced activation of human osteoarthritic
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50. Reginster JY, Rovati LC, Henrotin Y, et al. Author' s reply [correspondence]. Lancet, 2001, 357 (9252):1618.
51. Creamer P, Lethbridge-Cejku M, Hochberg MC. Factors associated with functional impairment in symptomatic knee osteoarthritis. Rheumatology (Oxford), 2000, 39(5):490-496.
52. Odding E, Valkenburg HA, Algra D, et al. Associations of radiological osteoarthritis of the hip and knee with locomotor disability in the Rotterdam Study. Ann Rheum Dis, 1998, 57(4) : 203-208.
53. Richy F, Bruyere 0, Ethgen 0, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med, 2003, 163:1514-1522.
54. Bruyere O, Honore A, Ethgen 0, et al. Correlation between radiographic severity of knee osteoarthritis and future disease progression. Results from a 3-year prospective, placebo-controlled study evaluating the effect of glucosamine sulfate. Osteoarthritis Cartilage, 2003, 11:1-5.
55. Adams JG, McAlindon T, Dimasi M, et al .Contribution of meniscal extrusion and cartilage loss to joint space narrowing in osteoarthritis. Clin Radiol, 1999, 54(8) :502-506.
56. Raskin JB. Gastrointestinal effects of nonsteroidal anti -inflammatory therapy. Am J Med,1999,106 Suppl, 5B:3S-12S.
57.Mandell BF. General tolerability and use of nonsteroidal??anti-inflammatory drugs. Am J Med, 1999,107 (6A) :72S-76S.
58. Herman JH, Appel AM, Khosla RC, et al. The in vitro effect of select classes of nonsteroidal antiinflammatory drugs on normal cartilage metabolism. J Rheumatol, 1986, 13(6):1014 -1018.
59. Rainsford KD. Profile and mechanisms of gastrointestinal and other side effects of nonsteroidal anti-inflammatory drugs Correspondence: Caroline M. Perry, Adis International Lim-(NSAIDs). Am J Med, 1999, 107(Suppl6A) :27S-36S.
60.Rashad S, Revell P, Hemingway A, et al. Effect of non-steroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet, 1989, 8662:519-521.
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63. Scott DL, Shipley M, Dawson A, et al. The clinical management of rheumatoid arthritis and osteoarthritis: strategies for improving clinical effectiveness. Br J Rheumatol, 1998, 37:546 -554.
64. Monauni T, Zenti MG, Cretti A, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes, 2000, 49:92635.
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66. Swinburne LM. Glucosamine sulphate and osteoarthritis. Lancet, 2001,357:1617.
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70. McAlindon T. Glucosamine for osteoarthritis: dawn of a new era? Lancet, 2001,27, 357:247.
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53. Richy F, Bruyere 0, Ethgen 0, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med, 2003, 163:1514-1522.
54. Bruyere O, Honore A, Ethgen 0, et al. Correlation between radiographic severity of knee osteoarthritis and future disease progression. Results from a 3-year prospective, placebo-controlled study evaluating the effect of glucosamine sulfate. Osteoarthritis Cartilage, 2003, 11:1-5.
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56. Raskin JB. Gastrointestinal effects of nonsteroidal anti -inflammatory therapy. Am J Med,1999,106 Suppl, 5B:3S-12S.
57.Mandell BF. General tolerability and use of nonsteroidal??anti-inflammatory drugs. Am J Med, 1999,107 (6A) :72S-76S.
58. Herman JH, Appel AM, Khosla RC, et al. The in vitro effect of select classes of nonsteroidal antiinflammatory drugs on normal cartilage metabolism. J Rheumatol, 1986, 13(6):1014 -1018.
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60.Rashad S, Revell P, Hemingway A, et al. Effect of non-steroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet, 1989, 8662:519-521.
61. Fung HB, Kirschenbaum HL. Selective cyclooxygenase-2 in hibitors for the treatment of arthritis. Clin Ther, 1999, 21 (7): 1131-1157.
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63. Scott DL, Shipley M, Dawson A, et al. The clinical management of rheumatoid arthritis and osteoarthritis: strategies for improving clinical effectiveness. Br J Rheumatol, 1998, 37:546 -554.
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65. Goldstein MR. Glucosamine sulphate and osteoarthritis . Lancet, 2001,357:16178.
66. Swinburne LM. Glucosamine sulphate and osteoarthritis. Lancet, 2001,357:1617.
67. Deal CL, Moskowitz RW. Nutraceuticals as therapeutic agents??in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheum Dis Clin North Am, 1999, 25 (2): 379-395.
68. Chard J, Dieppe P. Glucosamine for osteoarthritis: magic, hype, or confusion? It' s probably safe - but there' s no good evidence Br Med J, 2001, 322:1439-1440.
69. Halbekath J, Lehnert R, Wille H. Glucosamine sulphate and osteoarthritis. Lancet, 2001, 357:1617.
70. McAlindon T. Glucosamine for osteoarthritis: dawn of a new era? Lancet, 2001,27, 357:247.
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