The mechanism research of sodium hyaluronate to rabbit knee osteoarthritis based on metabolomics research_West China Medical Journal

Authors：

LAI Sike ¹ , CAO Chang ² , LI Jian ³ ,  LI Qi ³

1. West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
3. Department of Orthopedics/Sports Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LI Qi, Email: liqimm@163.com

Keywords：

Osteoarthritis; Sodium hyaluronate; Nuclear magnetic resonance; Metabolomics; Multivariate data analysis

DOI：

10.7507/1002-0179.201808068

Video：

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ObjectiveTo detect the metabolites of the serum and joint fluid from rabbits’ osteoarthritis model with ¹H nuclear magnetic resonance spectroscopy (NMR) technique, study the metabolic differences and connections of serum, synovial and cartilage of rabbits after the articular cavity injection of sodium hyaluronate, and explore osteoarthritis and metabolic mechanism in the process of treating sodium hyaluronate using sodium hyaluronate, thus provide new ideas and basis of the specific mechanisms in the treatment of osteoarthritis via sodium hyaluronate.MethodsWe selected 30 healthy New Zealand white rabbits, 6 months old, and randomly divided them into three groups as follows: blank control group, model phosphate buffer saline (PBS) liquid injection group and model injection of sodium hyaluronate group, with 10 rabbits in each group. Ten weeks after surgery, all experimental animals were put to death and observed in correlation studies regarding general condition, imaging examination, and histological examination. Metabolites ¹H NMR detection and data preprocessing were performed in the serum and joint fluid samples.ResultsThe results considering general condition, general sample observation, imaging examination and histology indicated advantages in sodium hyaluronate group over PBS group. Metabolomics analysis showed statistically significant changes of metabolites in the serum and joint fluid compared with the PBS group and the blank control group (P<0.05). According to the relevant ways of differences metabolites retrieval, analysis found that the effect of sodium hyaluronate on osteoarthritis might be related to protein biosynthesis, amino acid circulation, the metabolic process of pyruvic acid, gluconeogenesis and other metabolic pathways.ConclusionsBased on the research of ¹H-NMR metabolomics, the results suggest that the effect of sodium hyaluronate on osteoarthritis is mainly related with the activation of protein metabolism, abnormal lipid and energy metabolic pathways. This study provides new ideas and basis on the concrete mechanism in the treatment of knee osteoarthritis using sodium hyaluronate.

Citation： LAI Sike, CAO Chang, LI Jian, LI Qi. The mechanism research of sodium hyaluronate to rabbit knee osteoarthritis based on metabolomics research. West China Medical Journal, 2018, 33(9): 1153-1161. doi: 10.7507/1002-0179.201808068 Copy

1.	Martel-Pelletier J, Pelletier JP. Is osteoarthritis a disease involving only cartilage or other articular tissues?. Eklem Hastalik Cerrahisi, 2010, 21(1): 2-14.
2.	Atik OŞ, Tokgöz N. Do periarticular dense bone islands cause cartilage destruction?. Eklem Hastalik Cerrahisi, 2013, 24(1): 39-40.
3.	Ma J, Niu DS, Wan NJ, et al. Elevated chemerin levels in synovial fluid and synovial membrane from patients with knee osteoarthritis. Int J Clin Exp Pathol, 2015, 8(10): 13393-13398.
4.	Reichenbach S, Blank S, Rutjes AW, et al. Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis. Arthritis Rheum, 2007, 57(8): 1410-1418.
5.	Hunter DJ. Insights from imaging on the epidemiology and pathophysiology of osteoarthritis. Radiol Clin North Am, 2009, 47(4): 539-551.
6.	Nicholson JK, Lindon JC, Holmes E. ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica, 1999, 29(11): 1181-1189.
7.	Adams SB, Setton LA, Nettles DL. The role of metabolomics in osteoarthritis research. J Am Acad Orthop Surg, 2013, 21(1): 63-64.
8.	Vicky De Preter. Metabonomics and systems biology. Metabonomics methods and protocols. New York: Humana Press, 2015: 245-255.
9.	Moreland LW. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther, 2003, 5(2): 54-67.
10.	Zhu J, Lei P, Hu Y. Intraarticular hyaluronate injection for knee osteoarthritis-reconsider the rationale. Ann Transl Med, 2015, 3(15): 214.
11.	Peyron JG, Balazs EA. Preliminary clinical assessment of Na-hyaluronate injection into human arthritic joints. Pathol Biol (Paris), 1974, 22(8): 731-736.
12.	中华人民共和国国家质量监督检验检疫总局. GB 14925-2010: 实验动物环境及设施. 北京: 中国标准出版社, 2010.
13.	Hulth A, Lindberg L, Telhag H. Experimental osteoarthritis in rabbits. Preliminary report. Acta Orthop Scand, 1970, 41(5): 522-530.
14.	Xiao C, Hao F, Qin X, et al. An optimized buffer system for NMR-based urinary metabonomics with effective pH control, chemical shift consistency and dilution minimization. Analyst, 2009, 134(5): 916-925.
15.	Poulet B, de Souza R, Knights CB, et al. Modifications of gait as predictors of natural osteoarthritis progression in STR/Ort mice. Arthritis Rheumatol, 2014, 66(7): 1832-1842.
16.	Culley KL, Dragomir CL, Chang J, et al. Mouse models of osteoarthritis: surgical model of posttraumatic osteoarthritis induced by destabilization of the medial meniscus. Methods Mol Biol, 2015, 1226: 143-173.
17.	Dyke JP, Synan M, Ezell P, et al. Characterization of bone perfusion by dynamic contrast-enhanced magnetic resonance imaging and positron emission tomography in the Dunkin-Hartley Guinea pig model of advanced osteoarthritis. J Orthop Res, 2015, 33(3): 366-372.
18.	Lane NE, Thompson JM. Management of osteoarthritis in the primary-care setting: an evidence-based approach to treatment. Am J Med, 1997, 103(6a): 25S-30S.
19.	Muehleman C, Green J, Williams JM, et al. The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage. Osteoarthritis and Cartilage, 2002, 10(3): 226-233.
20.	Marijnissen AC, van Roermund PM, Verzijl N, et al. Steady progression of osteoarthritic features in the canine groove model. Osteoarthritis Cartilage, 2002, 10(4): 282-289.
21.	Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer, 2004, 4(7): 528-539.
22.	Pham T, Le Henanff A, Ravaud P, et al. Evaluation of the symptomatic and structural efficacy of a new hyaluronic acid compound, NRD101, in comparison with diacerein and placebo in a 1 year randomised controlled study in symptomatic knee osteoarthritis. Ann Rheum Dis, 2004, 63(12): 1611-1617.
23.	Kondo K, Jingushi S, Ohfuji S, et al. Factors associated with functional limitations in the daily living activities of Japanese hip osteoarthritis patients. Int J Rheum Dis, 2017, 20(10): 1372-1382.
24.	Jung S, Petelska A, Beldowski P, et al. Hyaluronic acid and phospholipid interactions useful for repaired articular cartilage surfaces-a mini review toward tribological surgical adjuvants. Colloid Polym Sci, 2017, 295(3): 403-412.
25.	McBride A, Khan HI, Aitken D, et al. Does cartilage volume measurement or radiographic osteoarthritis at baseline independently predict ten-year cartilage volume loss?. BMC Musculoskelet Disord, 2016: 54.
26.	Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol, 2007, 213(3): 626-634.
27.	Loeser RF, Goldring SR, Scanzello CR, et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum, 2012, 64(6): 1697-1707.
28.	Anderson DD, Chubinskaya S, Guilak F, et al. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J Orthop Res, 2011, 29(6): 802-809.
29.	Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol, 2011, 23(5): 492-496.
30.	Lotz M, Loeser RF. Effects of aging on articular cartilage homeostasis. Bone, 2012, 51(2, SI): 241-248.
31.	Zignego DL, Hilmer JK, June RK. Mechanotransduction in primary human osteoarthritic chondrocytes is mediated by metabolism of energy, lipids, and amino acids. J Biomech, 2015, 48(16): 4253-4261.
32.	Petursson F, Husa M, June R, et al. Linked decreases in liver kinase B1 and AMP-activated protein kinase activity modulate matrix catabolic responses to biomechanical injury in chondrocytes. Arthritis Res Ther, 2013, 15(4): R77.
33.	Zhang W, Likhodii S, Aref-Eshghi E, et al. Relationship between blood plasma and synovial fluid metabolite concentrations in patients with osteoarthritis. J Rheumatol, 2015, 42(5): 859-865.
34.	Chen R, Han S, Liu X, et al. Perturbations in amino acids and metabolic pathways in osteoarthritis patients determined by targeted metabolomics analysis. J Chromatogr B Analyt Technol Biomed Life Sci, 2018, 1085: 54-62.
35.	Adler N, Schoeniger A, Fuhrmann H. Polyunsaturated fatty acids influence inflammatory markers in a cellular model for canine osteoarthritis. J Anim Physiol Anim Nutr (Berl), 2018, 102(2): e623-e632.
36.	Wen ZH, Chang YC, Jean YH. Excitatory amino acid glutamate: role in peripheral nociceptive transduction and inflammation in experimental and clinical osteoarthritis. Osteoarthritis Cartilage, 2015, 23(11): 2009-2016.
37.	Batch BC, Shah SH, Newgard CB, et al. Branched chain amino acids are novel biomarkers for discrimination of metabolic wellness. Metabolism, 2013, 62(7): 961-969.
38.	Zhang W, Sun G, Aitken D, et al. Lysophosphatidylcholines to phosphatidylcholines ratio predicts advanced knee osteoarthritis. Rheumatology (Oxford), 2016, 55(9): 1566-1574.
39.	Zhai G, Randell EW, Rahman P. Metabolomics of osteoarthritis: emerging novel markers and their potential clinical utility. Rheumatology (Oxford), 2018. doi: 10.1093/rheumatology/kex497.
40.	Collins KH, Paul HA, Reimer RA, et al. Relationship between inflammation, the gut microbiota, and metabolic osteoarthritis development: studies in a rat model. Osteoarthritis Cartilage, 2015, 23(11): 1989-1998.
41.	Zhuo Q, Yang W, Chen JY, et al. Metabolic syndrome meets osteoarthritis. Nat Rev Rheumatol, 2012, 8(12): 729-737.
42.	Woods A, James CG, Wang G, et al. Control of chondrocyte gene expression by actin dynamics: a novel role of cholesterol/Ror-alpha signalling in endochondral bone growth. J Cell Mol Med, 2009, 13(9b): 3497-3516.
43.	Huang Z, Kraus VB. Does lipopolysaccharide-mediated inflammation have a role in OA?. Nat Rev Rheumatol, 2016, 12(2): 123-129.

1. Martel-Pelletier J, Pelletier JP. Is osteoarthritis a disease involving only cartilage or other articular tissues?. Eklem Hastalik Cerrahisi, 2010, 21(1): 2-14.
2. Atik OŞ, Tokgöz N. Do periarticular dense bone islands cause cartilage destruction?. Eklem Hastalik Cerrahisi, 2013, 24(1): 39-40.
3. Ma J, Niu DS, Wan NJ, et al. Elevated chemerin levels in synovial fluid and synovial membrane from patients with knee osteoarthritis. Int J Clin Exp Pathol, 2015, 8(10): 13393-13398.
4. Reichenbach S, Blank S, Rutjes AW, et al. Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis. Arthritis Rheum, 2007, 57(8): 1410-1418.
5. Hunter DJ. Insights from imaging on the epidemiology and pathophysiology of osteoarthritis. Radiol Clin North Am, 2009, 47(4): 539-551.
6. Nicholson JK, Lindon JC, Holmes E. ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica, 1999, 29(11): 1181-1189.
7. Adams SB, Setton LA, Nettles DL. The role of metabolomics in osteoarthritis research. J Am Acad Orthop Surg, 2013, 21(1): 63-64.
8. Vicky De Preter. Metabonomics and systems biology. Metabonomics methods and protocols. New York: Humana Press, 2015: 245-255.
9. Moreland LW. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther, 2003, 5(2): 54-67.
10. Zhu J, Lei P, Hu Y. Intraarticular hyaluronate injection for knee osteoarthritis-reconsider the rationale. Ann Transl Med, 2015, 3(15): 214.
11. Peyron JG, Balazs EA. Preliminary clinical assessment of Na-hyaluronate injection into human arthritic joints. Pathol Biol (Paris), 1974, 22(8): 731-736.
12. 中华人民共和国国家质量监督检验检疫总局. GB 14925-2010: 实验动物环境及设施. 北京: 中国标准出版社, 2010.
13. Hulth A, Lindberg L, Telhag H. Experimental osteoarthritis in rabbits. Preliminary report. Acta Orthop Scand, 1970, 41(5): 522-530.
14. Xiao C, Hao F, Qin X, et al. An optimized buffer system for NMR-based urinary metabonomics with effective pH control, chemical shift consistency and dilution minimization. Analyst, 2009, 134(5): 916-925.
15. Poulet B, de Souza R, Knights CB, et al. Modifications of gait as predictors of natural osteoarthritis progression in STR/Ort mice. Arthritis Rheumatol, 2014, 66(7): 1832-1842.
16. Culley KL, Dragomir CL, Chang J, et al. Mouse models of osteoarthritis: surgical model of posttraumatic osteoarthritis induced by destabilization of the medial meniscus. Methods Mol Biol, 2015, 1226: 143-173.
17. Dyke JP, Synan M, Ezell P, et al. Characterization of bone perfusion by dynamic contrast-enhanced magnetic resonance imaging and positron emission tomography in the Dunkin-Hartley Guinea pig model of advanced osteoarthritis. J Orthop Res, 2015, 33(3): 366-372.
18. Lane NE, Thompson JM. Management of osteoarthritis in the primary-care setting: an evidence-based approach to treatment. Am J Med, 1997, 103(6a): 25S-30S.
19. Muehleman C, Green J, Williams JM, et al. The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage. Osteoarthritis and Cartilage, 2002, 10(3): 226-233.
20. Marijnissen AC, van Roermund PM, Verzijl N, et al. Steady progression of osteoarthritic features in the canine groove model. Osteoarthritis Cartilage, 2002, 10(4): 282-289.
21. Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer, 2004, 4(7): 528-539.
22. Pham T, Le Henanff A, Ravaud P, et al. Evaluation of the symptomatic and structural efficacy of a new hyaluronic acid compound, NRD101, in comparison with diacerein and placebo in a 1 year randomised controlled study in symptomatic knee osteoarthritis. Ann Rheum Dis, 2004, 63(12): 1611-1617.
23. Kondo K, Jingushi S, Ohfuji S, et al. Factors associated with functional limitations in the daily living activities of Japanese hip osteoarthritis patients. Int J Rheum Dis, 2017, 20(10): 1372-1382.
24. Jung S, Petelska A, Beldowski P, et al. Hyaluronic acid and phospholipid interactions useful for repaired articular cartilage surfaces-a mini review toward tribological surgical adjuvants. Colloid Polym Sci, 2017, 295(3): 403-412.
25. McBride A, Khan HI, Aitken D, et al. Does cartilage volume measurement or radiographic osteoarthritis at baseline independently predict ten-year cartilage volume loss?. BMC Musculoskelet Disord, 2016: 54.
26. Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol, 2007, 213(3): 626-634.
27. Loeser RF, Goldring SR, Scanzello CR, et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum, 2012, 64(6): 1697-1707.
28. Anderson DD, Chubinskaya S, Guilak F, et al. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J Orthop Res, 2011, 29(6): 802-809.
29. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol, 2011, 23(5): 492-496.
30. Lotz M, Loeser RF. Effects of aging on articular cartilage homeostasis. Bone, 2012, 51(2, SI): 241-248.
31. Zignego DL, Hilmer JK, June RK. Mechanotransduction in primary human osteoarthritic chondrocytes is mediated by metabolism of energy, lipids, and amino acids. J Biomech, 2015, 48(16): 4253-4261.
32. Petursson F, Husa M, June R, et al. Linked decreases in liver kinase B1 and AMP-activated protein kinase activity modulate matrix catabolic responses to biomechanical injury in chondrocytes. Arthritis Res Ther, 2013, 15(4): R77.
33. Zhang W, Likhodii S, Aref-Eshghi E, et al. Relationship between blood plasma and synovial fluid metabolite concentrations in patients with osteoarthritis. J Rheumatol, 2015, 42(5): 859-865.
34. Chen R, Han S, Liu X, et al. Perturbations in amino acids and metabolic pathways in osteoarthritis patients determined by targeted metabolomics analysis. J Chromatogr B Analyt Technol Biomed Life Sci, 2018, 1085: 54-62.
35. Adler N, Schoeniger A, Fuhrmann H. Polyunsaturated fatty acids influence inflammatory markers in a cellular model for canine osteoarthritis. J Anim Physiol Anim Nutr (Berl), 2018, 102(2): e623-e632.
36. Wen ZH, Chang YC, Jean YH. Excitatory amino acid glutamate: role in peripheral nociceptive transduction and inflammation in experimental and clinical osteoarthritis. Osteoarthritis Cartilage, 2015, 23(11): 2009-2016.
37. Batch BC, Shah SH, Newgard CB, et al. Branched chain amino acids are novel biomarkers for discrimination of metabolic wellness. Metabolism, 2013, 62(7): 961-969.
38. Zhang W, Sun G, Aitken D, et al. Lysophosphatidylcholines to phosphatidylcholines ratio predicts advanced knee osteoarthritis. Rheumatology (Oxford), 2016, 55(9): 1566-1574.
39. Zhai G, Randell EW, Rahman P. Metabolomics of osteoarthritis: emerging novel markers and their potential clinical utility. Rheumatology (Oxford), 2018. doi: 10.1093/rheumatology/kex497.
40. Collins KH, Paul HA, Reimer RA, et al. Relationship between inflammation, the gut microbiota, and metabolic osteoarthritis development: studies in a rat model. Osteoarthritis Cartilage, 2015, 23(11): 1989-1998.
41. Zhuo Q, Yang W, Chen JY, et al. Metabolic syndrome meets osteoarthritis. Nat Rev Rheumatol, 2012, 8(12): 729-737.
42. Woods A, James CG, Wang G, et al. Control of chondrocyte gene expression by actin dynamics: a novel role of cholesterol/Ror-alpha signalling in endochondral bone growth. J Cell Mol Med, 2009, 13(9b): 3497-3516.
43. Huang Z, Kraus VB. Does lipopolysaccharide-mediated inflammation have a role in OA?. Nat Rev Rheumatol, 2016, 12(2): 123-129.

West China Medical Journal

The mechanism research of sodium hyaluronate to rabbit knee osteoarthritis based on metabolomics research

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