臺灣博碩士論文加值系統

骨關節炎 (OA) 已經變成常見的移動障礙的疾病，在銀髮族以及肥胖患者較常見。性別、肥胖程度、曾創傷嚴重度以及遺傳都是OA 的風險因子之一。肥胖所造成的 OA 對關節會造成關節的機械壓力、關節軟骨降解、骨質流失以及發炎反應。褐藻醣膠是由海藻褐藻所萃取得出之含硫酸基團的多醣體，對生理功能已被研究出有抗發炎、抗氧化、抗腫瘤、抗病毒、抗凝血效果及具有免疫調節的功能。本研究探討褐藻醣膠對於高脂飲食肥胖伴隨著手術誘導 OA 雄性大鼠的影響。 OA 的手術是透過十字韌帶之切斷及半月軟骨之部分去除 (ACLT + MMx)。雄性 Sprague Dawley大白鼠在ACLT+MMx 手術開刀前給予 4 週期的 40% 高脂飲食誘導肥胖。手術後，OA組透過管餵方式給予不同劑量的褐藻醣膠溶液，分為 32 mg/kg, 64 mg/kg and 320 mg/kg，餵食期間為 40 日與高脂飲食同時餵食。由結果觀察到 OA 組的關節腫脹度有改善以及後腳雙足平衡也改善。體重與體脂肪也有顯著的下降但不影響攝食量。分析血漿之脂肪指標得知對於高密度脂蛋白膽固醇之含量無明顯效果但在低密度脂蛋白膽固醇、三酸甘油脂及總膽固醇的濃度有改善的情形。另外，雙足平衡測試結果顯示餵食褐藻醣膠的 OA 組別有改善的情形。因此推測餵食褐藻醣膠可以有效改善肥胖伴隨著 OA 的情形。

Osteoarthritis (OA) has become one of the most common disabilities among elders, especially in female and those with metabolic diseases. The risk factors involved in OA include gender, obesity, previous injury, and heredity. Obesity-related OA is attributed to joint loading, cartilage disintegration, bone loss along with inflammation. Fucoidan is a sulfated polysaccharide extracted from brown algae. It has been studied for its antitumor, antiviral, anticoagulation and immunomodulation. In this study, we investigate the effect of fucoidan in surgery-induced OA on diet-induced obesity male rats. OA was induced by anterior cruciate ligament transection (ACLT) and medial meniscectomy (MMx) method. Male Sprague Dawley (SD) rats were fed 40% high fat diet for 4 weeks to induce obesity before ACLT+MMx to initiate OA. OA rats were administered intragastrically with water or fucoidan P.O. in three different concentration, 32 mg/kg, 64 mg/kg, and 320 mg/kg after surgeries for 40 days with high-fat diet in parallel. We observed that the swelling in the OA knee was alleviated and the hind paw weight distribution was rectified after feeding fucoidan, with significant effect on body weight and body fat reduction and plasma lipid were also analyzed. Our result indicated no significant variation on HDL-cholesterol, but reduced plasma triglycerides, total cholesterol, and LDL-cholesterol level. In addition, weight-bearing tests showed some improvement on fucoidan-fed groups. Our result suggests that the feeding of fucoidan may potentially improve meniscal/ligamentous injury of obesity induced OA.

Abstract I
摘要 II
目錄 III
圖目錄 V
表目錄 VI
壹. 前言 1
貳. 文獻回顧 3
a. 肥胖 3
i. 全球與台灣之肥胖狀況 3
ii. 定義，造成原因，判定方法 3
iii. 肥胖之相關疾病 4
b. 骨關節炎 6
i. 定義與現況 6
ii. 主要發生原因與風險因子 6
iii. 骨關節炎之惡化 6
iv. 目前治療選項及其優缺點 7
c. 肥胖與骨關節炎的關係 9
d. 褐藻醣膠 11
i. 介紹 11
iii. 生理功效 12
參. 實驗設計 14
肆. 實驗材料 15
a. 實驗材料 15
b. 實驗動物 15
c. 實驗飼料 15
d. 藥品儀器 15
i. 藥物 15
ii. 器材設備 16
伍. 實驗方法 18
a. 動物實驗 18
i. 實驗動物飼養 18
ii. 實驗動物模式之誘導方法 18
iii. 實驗動物模式之分析及確認 19
iv. 實驗動物之犧牲 19
b. 實驗動物之後續分析及統計方法 20
i. 血液分析 20
ii. 關節分析 25
c. 統計方法 26
陸. 實驗結果 27
a. 褐藻醣膠對體脂肪增生之影響 27
b. 褐藻醣膠對發炎指標及抗氧化酵素之影響 27
c. 褐藻醣膠對骨關節恢復之影響 28
捌. 討論 29
玖. 結論 31
壹拾. 參考文獻 31
壹拾壹. 圖表 37
壹拾貳. 附錄 50

Aisa, Y., Miyakawa, Y., Nakazato, T., Shibata, H., Saito, K., Ikeda, Y., Kizaki, M., 2005. Fucoidan induces apoptosis of human HS-sultan cells accompanied by activation of caspase-3 and down-regulation of ERK pathways. American Journal of Hematology 78, 7-14.
Ale, M.T., Mikkelsen, J.D., Meyer, A.S., 2012. Designed optimization of a single-step extraction of fucose-containing sulfated polysaccharides from Sargassum sp. Journal of applied phycology 24, 715-723.
American Cancer Society , A., 2017. Cancer Facts & Figures. American Cancer Society, Atlanta.
Anderson, J.J., Felson, D.T., 1988. Factors associated with osteoarthritis of the knee in the first national Health and Nutrition Examination Survey (HANES I) evidence for an association with overweight, race, and physical demands of work. American journal of epidemiology 128, 179-189.
Bao, J.-p., Chen, W.-p., Feng, J., Hu, P.-f., Shi, Z.-l., Wu, L.-d., 2010. Leptin plays a catabolic role on articular cartilage. Molecular biology reports 37, 3265-3272.
Bayliss, E.A., Ellis, J.L., Steiner, J.F., 2007. Barriers to self-management and quality-of-life outcomes in seniors with multimorbidities. The Annals of Family Medicine 5, 395-402.
Ben-Eliezer, M., Phillip, M., Gat-Yablonski, G., 2007. Leptin regulates chondrogenic differentiation in ATDC5 cell-line through JAK/STAT and MAPK pathways. Endocrine 32, 235-244.
Bendele, A., 2001. Animal models of osteoarthritis. Journal of Musculoskeletal and Neuronal Interactions 1, 363-376.
Bilan, M.I., Grachev, A.A., Shashkov, A.S., Nifantiev, N.E., Usov, A.I., 2006. Structure of a fucoidan from the brown seaweed Fucus serratus L. Carbohydrate Research 341, 238-245.
Bilan, M.I., Grachev, A.A., Ustuzhanina, N.E., Shashkov, A.S., Nifantiev, N.E., Usov, A.I., 2002. Structure of a fucoidan from the brown seaweed Fucus evanescens C.Ag. Carbohydr Res 337, 719-730.
Black, W., Dewar, E., Woodward, F., 1952. Laboratory-scale isolation of fucoidan from brown marine algae: Manufacture of algal chemicals. IV. Journal of the Science of Food and Agriculture 3, 122-129.
Bokarewa, M., Nagaev, I., Dahlberg, L., Smith, U., Tarkowski, A., 2005. Resistin, an adipokine with potent proinflammatory properties. The Journal of Immunology 174, 5789-5795.
Chandalia, M., Garg, A., Lutjohann, D., von Bergmann, K., Grundy, S.M., Brinkley, L.J., 2000. Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus. The New England Journal of Medicine 342, 1392-1398.
Chang, H.C., Yang, H.C., Chang, H.Y., Yeh, C.J., Chen, H.H., Huang, K.C., Pan, W.H., 2017. Morbid obesity in Taiwan: Prevalence, trends, associated social demographics, and lifestyle factors. Plos One 12, e0169577.
Chizhov, A.O., Dell, A., Morris, H.R., Haslam, S.M., McDowell, R.A., Shashkov, A.S., Nifant'ev, N.E., Khatuntseva, E.A., Usov, A.I., 1999a. A study of fucoidan from the brown seaweed Chorda filum. Carbohydrate Research 320, 108-119.
Chizhov, A.O., Dell, A., Morris, H.R., Haslam, S.M., McDowell, R.A., Shashkov, A.S., Nifant’ev, N.E., Khatuntseva, E.A., Usov, A.I., 1999b. A study of fucoidan from the brown seaweed Chorda filum. Carbohydrate Research 320, 108-119.
Chu, R., Madison, L.D., Lin, Y., Kopp, P., Rao, M.S., Jameson, J.L., Reddy, J.K., 1995. Thyroid hormone (T3) inhibits ciprofibrate-induced transcription of genes encoding beta-oxidation enzymes: cross talk between peroxisome proliferator and T3 signaling pathways. Proceedings of the National Academy of Sciences 92, 11593-11597.
Dequeker, J., 1999. The inverse relationship between osteoporosis and osteoarthritis. Rheumaderm. Springer, pp. 419-422.
Dobashi, K., Nishino, T., Fujihara, M., Nagumo, T., 1989. Isolation and preliminary characterization of fucose-containing sulfated polysaccharides with blood-anticoagulant activity from the brown seaweed Hizikia fusiforme. Carbohydrate Research 194, 315-320.
Dodge, G., Jimenez, S., 2003. Glucosamine sulfate modulates the levels of aggrecan and matrix metalloproteinase-3 synthesized by cultured human osteoarthritis articular chondrocytes. Osteoarthritis and Cartilage 11, 424-432.
Du Plessis, S.S., Cabler, S., McAlister, D.A., Sabanegh, E., Agarwal, A., 2010. The effect of obesity on sperm disorders and male infertility. Nature Reviews Urology 7, 153-161.
Dumond, H., Presle, N., Terlain, B., Mainard, D., Loeuille, D., Netter, P., Pottie, P., 2003. Evidence for a key role of leptin in osteoarthritis. Arthritis & Rheumatology 48, 3118-3129.
Fain, J.N., 2006. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitamins and Hormones 74, 443-477.
Felson, D.T., 2006. Clinical practice. Osteoarthritis of the knee. The New England Journal of Medicine 354, 841-848.
Figenschau, Y., Knutsen, G., Shahazeydi, S., Johansen, O., Sveinbjörnsson, B., 2001. Human articular chondrocytes express functional leptin receptors. Biochemical and Biophysical Research Communications 287, 190-197.
Flannery, C.R., Little, C.B., Hughes, C.E., Curtis, C.L., Caterson, B., Jones, S.A., 2000. IL-6 and its soluble receptor augment aggrecanase-mediated proteoglycan catabolism in articular cartilage. Matrix Biology 19, 549-553.
Fujisawa, T., Hattori, T., Takahashi, K., Kuboki, T., Yamashita, A., Takigawa, M., 1999. Cyclic mechanical stress induces extracellular matrix degradation in cultured chondrocytes via gene expression of matrix metalloproteinases and interleukin-1. The Journal of Biochemistry 125, 966-975.
Goldring, M.B., Goldring, S.R., 2007. Osteoarthritis. Journal of Cellular Physiology 213, 626-634.
Gonzalez-Fuentes, A.M., Green, D.M., Rossen, R.D., Ng, B., 2010. Intra-articular hyaluronic acid increases cartilage breakdown biomarker in patients with knee osteoarthritis. Clinical Rheumatology 29, 619-624.
Gosset, M., Berenbaum, F., Salvat, C., Sautet, A., Pigenet, A., Tahiri, K., Jacques, C., 2008. Crucial role of visfatin/pre–B cell colony‐enhancing factor in matrix degradation and prostaglandin E2 synthesis in chondrocytes: Possible influence on osteoarthritis. Arthritis & Rheumatology 58, 1399-1409.
Hahn, T., Lang, S., Ulber, R., Muffler, K., 2012. Novel procedures for the extraction of fucoidan from brown algae. Process biochemistry 47, 1691-1698.
Haneji, K., Matsuda, T., Tomita, M., Kawakami, H., Ohshiro, K., Uchihara, J.N., Masuda, M., Takasu, N., Tanaka, Y., Ohta, T., Mori, N., 2005. Fucoidan extracted from Cladosiphon okamuranus Tokida induces apoptosis of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells. Nutrition and Cancer 52, 189-201.
Hashimoto, S., Creighton-Achermann, L., Takahashi, K., Amiel, D., Coutts, R., Lotz, M., 2002. Development and regulation of osteophyte formation during experimental osteoarthritis. Osteoarthritis and Cartilage 10, 180-187.
Hayami, T., Pickarski, M., Zhuo, Y., Wesolowski, G.A., Rodan, G.A., Duong, L.T., 2006. Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone 38, 234-243.
Hayashi, K., Nakano, T., Hashimoto, M., Kanekiyo, K., Hayashi, T., 2008. Defensive effects of a fucoidan from brown alga Undaria pinnatifida against herpes simplex virus infection. International Immunopharmacology 8, 109-116.
Haywood, L., McWilliams, D., Pearson, C., Gill, S., Ganesan, A., Wilson, D., Walsh, D., 2003. Inflammation and angiogenesis in osteoarthritis. Arthritis & Rheumatology 48, 2173-2177.
Huang, L., Wen, K., Gao, X., Liu, Y., 2010. Hypolipidemic effect of fucoidan from Laminaria japonica in hyperlipidemic rats. Pharmaceutical Biology 48, 422-426.
Kanata, S., Akagi, M., Nishimura, S., Hayakawa, S., Yoshida, K., Sawamura, T., Munakata, H., Hamanishi, C., 2006. Oxidized LDL binding to LOX-1 upregulates VEGF expression in cultured bovine chondrocytes through activation of PPAR-γ. Biochemical and biophysical research communications 348, 1003-1010.
Kanda, H., Tateya, S., Tamori, Y., Kotani, K., Hiasa, K., Kitazawa, R., Kitazawa, S., Miyachi, H., Maeda, S., Egashira, K., Kasuga, M., 2006. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. Journal of Clinical Investigation 116, 1494-1505.
Kawano, N., Egashira, Y., Sanada, H., 2007. Effect of dietary fiber in edible seaweeds on the development of D-galactosamine-induced hepatopathy in rats. Journal of Nutritional Science and Vitaminology 53, 446-450.
Kawasaki, N., Asada, R., Saito, A., Kanemoto, S., Imaizumi, K., 2012. Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Scientific Reports 2, 799.
Kerkhof, H.J., Lories, R.J., Meulenbelt, I., Jonsdottir, I., Valdes, A.M., Arp, P., Ingvarsson, T., Jhamai, M., Jonsson, H., Stolk, L., Thorleifsson, G., Zhai, G., Zhang, F., Zhu, Y., van der Breggen, R., Carr, A., Doherty, M., Doherty, S., Felson, D.T., Gonzalez, A., Halldorsson, B.V., Hart, D.J., Hauksson, V.B., Hofman, A., Ioannidis, J.P., Kloppenburg, M., Lane, N.E., Loughlin, J., Luyten, F.P., Nevitt, M.C., Parimi, N., Pols, H.A., Rivadeneira, F., Slagboom, E.P., Styrkarsdottir, U., Tsezou, A., van de Putte, T., Zmuda, J., Spector, T.D., Stefansson, K., Uitterlinden, A.G., van Meurs, J.B., 2010. A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22. Arthritis & Rheumatology 62, 499-510.
Kim, M.J., Jeon, J., Lee, J.S., 2014. Fucoidan Prevents High‐Fat Diet‐Induced Obesity in Animals by Suppression of Fat Accumulation. Phytotherapy Research 28, 137-143.
Kim, S.-J., Ju, J.-W., Oh, C.-D., Yoon, Y.-M., Song, W.K., Kim, J.-H., Yoo, Y.J., Bang, O.-S., Kang, S.-S., Chun, J.-S., 2002. ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. Journal of Biological Chemistry 277, 1332-1339.
Ko, F.C., Dragomir, C., Plumb, D.A., Goldring, S.R., Wright, T.M., Goldring, M.B., Meulen, M.C., 2013. In vivo cyclic compression causes cartilage degeneration and subchondral bone changes in mouse tibiae. Arthritis & Rheumatology 65, 1569-1578.
Lambert, C., Mathy-Hartert, M., Dubuc, J.-E., Montell, E., Vergés, J., Munaut, C., Noël, A., Henrotin, Y., 2012. Characterization of synovial angiogenesis in osteoarthritis patients and its modulation by chondroitin sulfate. Arthritis research & therapy 14, R58.
Lapshina, L., Reunov, A., Nagorskaya, V., Zvyagintseva, T., Shevchenko, N., 2006. Inhibitory effect of fucoidan from brown alga Fucus evanescens on the spread of infection induced by tobacco mosaic virus in tobacco leaves of two cultivars. Russian Journal of Plant Physiology 53, 246-251.
Largo, R., Alvarez-Soria, M., Dıez-Ortego, I., Calvo, E., Sanchez-Pernaute, O., Egido, J., Herrero-Beaumont, G., 2003. Glucosamine inhibits IL-1β-induced NFκB activation in human osteoarthritic chondrocytes. Osteoarthritis and Cartilage 11, 290-298.
Lawrence, R.C., Felson, D.T., Helmick, C.G., Arnold, L.M., Choi, H., Deyo, R.A., Gabriel, S., Hirsch, R., Hochberg, M.C., Hunder, G.G., Jordan, J.M., Katz, J.N., Kremers, H.M., Wolfe, F., National Arthritis Data, W., 2008. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis & Rheumatology 58, 26-35.
Lee, J., Ort, T., Ma, K., Picha, K., Carton, J., Marsters, P., Lohmander, L., Baribaud, F., Song, X.-Y., Blake, S., 2009. Resistin is elevated following traumatic joint injury and causes matrix degradation and release of inflammatory cytokines from articular cartilage in vitro. Osteoarthritis and Cartilage 17, 613-620.
Lefebvre, V., Peeters-Joris, C., Vaes, G., 1990. Modulation by interleukin 1 and tumor necrosis factor alpha of production of collagenase, tissue inhibitor of metalloproteinases and collagen types in differentiated and dedifferentiated articular chondrocytes. Biochimica et Biophysica Acta 1052, 366-378.
Legendre, F., Dudhia, J., Pujol, J.P., Bogdanowicz, P., 2003. JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression. The Journal of Biological Chemistry 278, 2903-2912.
Li, B., Lu, F., Wei, X., Zhao, R., 2008. Fucoidan: structure and bioactivity. Molecules 13, 1671-1695.
Li, D., Xu, R., Zhou, W., Sheng, X., Yang, A., Cheng, J., 2002. Effects of fucoidan extracted from brown seaweed on lipid peroxidation in mice. Acta Nutrimenta Sinica 24, 389-392.
Li, D., Xu, Z., Huang, L., Wang, H., Zhang, S., 2001. Effect of fucoidan of L. japonica on rats with hyperlipidaemia. Journal of Food Science 22, 92-95.
Li, D., Xu, Z., Zhang, S., 1999. Prevention and cure of fucoidan of L. japonica on mice with hypercholesterolemia. Journal of Food Science 20, 45-46.
Li, Y., Xu, L., Olsen, B.R., 2007. Lessons from genetic forms of osteoarthritis for the pathogenesis of the disease. Osteoarthritis and Cartilage 15, 1101-1105.
Lim, B.O., Yamada, K., Nonaka, M., Kuramoto, Y., Hung, P., Sugano, M., 1997. Dietary fibers modulate indices of intestinal immune function in rats. Journal of Nutrition 127, 663-667.
Liu, J.M., Bignon, J., Haroun-Bouhedja, F., Bittoun, P., Vassy, J., Fermandjian, S., Wdzieczak-Bakala, J., Boisson-Vidal, C., 2005. Inhibitory effect of fucoidan on the adhesion of adenocarcinoma cells to fibronectin. Anticancer Research 25, 2129-2133.
Lohmander, L.S., Ostenberg, A., Englund, M., Roos, H., 2004. High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury. Arthritis & Rheumatology 50, 3145-3152.
Lumeng, C.N., Bodzin, J.L., Saltiel, A.R., 2007. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. Journal of Clinical Investigation 117, 175-184.
Mandal, P., Mateu, C.G., Chattopadhyay, K., Pujol, C.A., Damonte, E.B., Ray, B., 2007. Structural features and antiviral activity of sulphated fucans from the brown seaweed Cystoseira indica. Antiviral Chemistry and Chemotherapy 18, 153-162.
Mankin, H.J., Dorfman, H., Lippiello, L., Zarins, A., 1971. Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data. The Journal of Bone and Joint Surgery. American Volume 53, 523-537.
Martel-Pelletier, J., McCollum, R., Fujimoto, N., Obata, K.i., Cloutier, J.-M., Pelletier, J.-P., 1994. Excess of metalloproteases over tissue inhibitor of metalloprotease may contribute to cartilage degradation in osteoarthritis and rheumatoid arthritis. Laboratory investigation; a journal of technical methods and pathology 70, 807-815.
Maruyama, H., Tamauchi, H., Iizuka, M., Nakano, T., 2006. The role of NK cells in antitumor activity of dietary fucoidan from Undaria pinnatifida sporophylls (Mekabu). Planta Medica 72, 1415-1417.
Masayuki, A., Tsuji, M., Tsuchiya, H., Murayama, M., Ogawa, M., Yanaki, H., Hayatake, R., Oguchi, K., 2014. Protective Effects of Fucoidan Against Interleukin-1β-induced Inflammation in SW982 Human Synovial Cells. The Showa University Journal of Medical Sciences 26, 47-56.
McHugh, D., 2003. A guide to the seaweed industry FAO Fisheries Technical Paper 441. Food and Agriculture Organization of the United Nations, Rome.
Mengshol, J.A., Vincenti, M.P., Coon, C.I., Barchowsky, A., Brinckerhoff, C.E., 2000. Interleukin‐1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c‐jun N‐terminal kinase, and nuclear factor κB: Differential regulation of collagenase 1 and collagenase 3. Arthritis & Rheumatology 43, 801-811.
NHLBI, 2017. Health Topics - Overweight and Obesity. Bethesda, U.S.A.
Nishino, T., Yokoyama, G., Dobashi, K., Fujihara, M., Nagumo, T., 1989. Isolation, purification, and characterization of fucose-containing sulfated polysaccharides from the brown seaweed Ecklonia kurome and their blood-anticoagulant activities. Carbohydrate Research 186, 119-129.
Otero, M., Lago, R., Lago, F., Reino, J.J.G., Gualillo, O., 2005. Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: synergistic effect of leptin with interleukin-1. Arthritis Research & Therapy 7, R581.
Pelletier, J.P., McCollum, R., Cloutier, J.M., Martel-Pelletier, J., 1995. Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process. Journal of Rheumatology Supplement 43, 109-114.
Percival, E., Ross, A., 1950. 145. Fucoidin. Part I. The isolation and purification of fucoidin from brown seaweeds. Journal of the Chemical Society (Resumed), 717-720.
Poree, B., Kypriotou, M., Chadjichristos, C., Beauchef, G., Renard, E., Legendre, F., Melin, M., Gueret, S., Hartmann, D.J., Mallein-Gerin, F., Pujol, J.P., Boumediene, K., Galera, P., 2008. Interleukin-6 (IL-6) and/or soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1.Sp3 ratio and of the binding activity of both factors to the COL2A1 promoter. The Journal of Biological Chemistry 283, 4850-4865.
Pritzker, K., Gay, S., Jimenez, S., Ostergaard, K., Pelletier, J.-P., Revell, P., Salter, D., Van den Berg, W., 2006. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis and Cartilage 14, 13-29.
Pufe, T., Harde, V., Petersen, W., Goldring, M.B., Tillmann, B., Mentlein, R., 2004. Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. The Journal of Pathology 202, 367-374.
Reboul, P., Pelletier, J.P., Tardif, G., Cloutier, J.M., Martel-Pelletier, J., 1996. The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis. Journal of Clinical Investigation 97, 2011-2019.
Roos, E.M., Ostenberg, A., Roos, H., Ekdahl, C., Lohmander, L.S., 2001. Long-term outcome of meniscectomy: symptoms, function, and performance tests in patients with or without radiographic osteoarthritis compared to matched controls. Osteoarthritis Cartilage 9, 316-324.
Ryu, J.H., Yang, S., Shin, Y., Rhee, J., Chun, C.H., Chun, J.S., 2011. Interleukin-6 plays an essential role in hypoxia-inducible factor 2alpha-induced experimental osteoarthritic cartilage destruction in mice. Arthritis & Rheumatology 63, 2732-2743.
Saklatvala, J., 1986. Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 322, 547-549.
Seguin, C.A., Bernier, S.M., 2003. TNFalpha suppresses link protein and type II collagen expression in chondrocytes: Role of MEK1/2 and NF-kappaB signaling pathways. Journal of Cellular Physiology 197, 356-369.
Shi, Z., Guo, Y., Wang, Z., 2000. Pharmacological activity of fucoidan from Laminaria japonic. Journal of Shanghai Fisheries University 9, 268-271.
Shu, Z., Shi, X., Nie, D., Guan, B., 2015. Low-Molecular-Weight Fucoidan Inhibits the Viability and Invasiveness and Triggers Apoptosis in IL-1β-Treated Human Rheumatoid Arthritis Fibroblast Synoviocytes. Inflammation 38, 1777-1786.
Song, J., Xu, Y., Zhang, H., 2000. Immunomodulation action of sulfate polysaccharide of Laminaria japonica on peritoneal macrophages of mice. Chinese Journal of Immunology 16, 70-70.
Srikanth, V.K., Fryer, J.L., Zhai, G., Winzenberg, T.M., Hosmer, D., Jones, G., 2005. A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage 13, 769-781.
Taube, A., Schlich, R., Sell, H., Eckardt, K., Eckel, J., 2012. Inflammation and metabolic dysfunction: links to cardiovascular diseases. American Journal of Physiology-Heart and Circulatory Physiology 302, H2148-H2165.
Thijssen, E., van Caam, A., van der Kraan, P.M., 2015. Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis. Rheumatology 54, 588-600.
Tong, K.-M., Shieh, D.-C., Chen, C.-P., Tzeng, C.-Y., Wang, S.-P., Huang, K.-C., Chiu, Y.-C., Fong, Y.-C., Tang, C.-H., 2008. Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion of NF-κB/p300 binding in human synovial fibroblasts. Cellular signalling 20, 1478-1488.
Tsai, W.-Y., Wu, J.-L., Liu, C.-C., Cherng, C.-H., Tsai, R.-Y., Jean, Y.-H., Wong, C.-S., 2013. Early intraarticular injection of hyaluronic acid attenuates osteoarthritis progression in anterior cruciate ligament-transected rats. Connective tissue research 54, 49-54.
Um, S.H., D'Alessio, D., Thomas, G., 2006. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3, 393-402.
Ushiyama, T., Chano, T., Inoue, K., Matsusue, Y., 2003. Cytokine production in the infrapatellar fat pad: another source of cytokines in knee synovial fluids. Annals of the rheumatic diseases 62, 108-112.
van Dielen, F.M., van't Veer, C., Schols, A.M., Soeters, P.B., Buurman, W.A., Greve, J.W., 2001. Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals. International Journal of Obesity and Related Metabolic Disorders 25, 1759-1766.
Vincenti, M.P., Brinckerhoff, C.E., 2001. Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Research & Therapy 4, 157.
Walsh, A.M., Sweeney, T., O'Shea, C.J., Doyle, D.N., O'Doherty, J.V., 2013. Effect of dietary laminarin and fucoidan on selected microbiota, intestinal morphology and immune status of the newly weaned pig. British Journal of Nutrition 110, 1630-1638.
Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R.L., Ferrante, A.W., Jr., 2003. Obesity is associated with macrophage accumulation in adipose tissue. Journal of Clinical Investigation 112, 1796-1808.
WHO, 2015. Obesity and overweight. Fact sheet No 311. 2015. Geneva, Switzerland.
Widmyer, M.R., Utturkar, G.M., Leddy, H.A., Coleman, J.L., Spritzer, C.E., Moorman, C.T., 3rd, DeFrate, L.E., Guilak, F., 2013. High body mass index is associated with increased diurnal strains in the articular cartilage of the knee. Arthritis & Rheumatology 65, 2615-2622.
Yang, J.W., Yoon, S.Y., Oh, S.J., Kim, S.K., Kang, K.W., 2006. Bifunctional effects of fucoidan on the expression of inducible nitric oxide synthase. Biochemical and Biophysical Research Communications 346, 345-350.
Yang, W.-H., Liu, S.-C., Tsai, C.-H., Fong, Y.-C., Wang, S.-J., Chang, Y.-S., Tang, C.-H., 2013. Leptin induces IL-6 expression through OBRl receptor signaling pathway in human synovial fibroblasts. Plos One 8, e75551.
Zhang, Q., Yu, P., Zhou, G., Li, Z.-E., Xu, Z.-H., 2003. Studies on antioxidant activities of fucoidan from Laminaria japonica. Chinese Traditional and Herbal Drugs 34, 824-826.
Zhang, Y., Jordan, J.M., 2010. Epidemiology of osteoarthritis. Clinics in Geriatric Medicine 26, 355-369.
Zhang, Z., Xing, X., Hensley, G., Chang, L.W., Liao, W., Abu‐Amer, Y., Sandell, L.J., 2010. Resistin induces expression of proinflammatory cytokines and chemokines in human articular chondrocytes via transcription and messenger RNA stabilization. Arthritis & Rheumatology 62, 1993-2003.
衛生福利部國民健康署, 2016. 身體質量指數 BMI. 衛生福利部國民健康署 臺北，台灣