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Published in: BMC Musculoskeletal Disorders 1/2008

Open Access 01-12-2008 | Research article

Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants

Authors: EJ Uitterlinden, JLM Koevoet, CF Verkoelen, SMA Bierma-Zeinstra, H Jahr, H Weinans, JAN Verhaar, GJVM van Osch

Published in: BMC Musculoskeletal Disorders | Issue 1/2008

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Abstract

Background

Glucosamine (GlcN) used by patients with osteoarthritis was demonstrated to reduce pain, but the working mechanism is still not clear. Viscosupplementation with hyaluronic acid (HA) is also described to reduce pain in osteoarthritis. The synthesis of HA requires GlcN as one of its main building blocks. We therefore hypothesized that addition of GlcN might increase HA production by synovium tissue.

Methods

Human osteoarthritic synovium explants were obtained at total knee surgery and pre-cultured for 1 day. The experimental conditions consisted of a 2 days continuation of the culture with addition of N-Acetyl-glucosamine (GlcN-Ac; 5 mM), glucosamine-hydrochloride (GlcN-HCl; 0.5 and 5 mM), glucose (Gluc; 0.5 and 5 mM). Hereafter HA production was measured in culture medium supernatant using an enzyme-linked binding protein assay. Real time RT-PCR was performed for hyaluronic acid synthase (HAS) 1, 2 and 3 on RNA isolated from the explants.

Results

0.5 mM and 5 mM GlcN-HCl significantly increased HA production compared to control (approximately 2 – 4-fold), whereas GlcN-Ac had no significant effect. Addition of 5 mM Gluc also increased HA production (approximately 2-fold), but 0.5 mM Gluc did not. Gene expression of the HA forming enzymes HAS 1, 2 and 3 was not altered by the addition of GlcN or Gluc.

Conclusion

Our data suggest that exogenous GlcN can increase HA production by synovium tissue and is more effective at lower concentrations than Gluc. This might indicate that GlcN exerts its potential analgesic properties through stimulation of synovial HA production.
Appendix
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Literature
1.
go back to reference Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO, Weisman MH, Jackson CG: Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006, 354 (8): 795-808. 10.1056/NEJMoa052771.CrossRefPubMed Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO, Weisman MH, Jackson CG: Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006, 354 (8): 795-808. 10.1056/NEJMoa052771.CrossRefPubMed
2.
go back to reference Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, Henrotin Y, Dacre JE, Gossett C: Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001, 357 (9252): 251-256. 10.1016/S0140-6736(00)03610-2.CrossRefPubMed Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, Henrotin Y, Dacre JE, Gossett C: Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001, 357 (9252): 251-256. 10.1016/S0140-6736(00)03610-2.CrossRefPubMed
3.
go back to reference Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC: Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002, 162 (18): 2113-2123. 10.1001/archinte.162.18.2113.CrossRefPubMed Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC: Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002, 162 (18): 2113-2123. 10.1001/archinte.162.18.2113.CrossRefPubMed
4.
go back to reference Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G: Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006, CD005321-2 Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G: Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006, CD005321-2
5.
go back to reference Uitterlinden EJ, Jahr H, Koevoet JL, Jenniskens YM, Bierma-Zeinstra SM, Degroot J, Verhaar JA, Weinans H, van Osch GJ: Glucosamine decreases expression of anabolic and catabolic genes in human osteoarthritic cartilage explants. Osteoarthritis Cartilage. 2006, 14 (3): 250-257. 10.1016/j.joca.2005.10.001.CrossRefPubMed Uitterlinden EJ, Jahr H, Koevoet JL, Jenniskens YM, Bierma-Zeinstra SM, Degroot J, Verhaar JA, Weinans H, van Osch GJ: Glucosamine decreases expression of anabolic and catabolic genes in human osteoarthritic cartilage explants. Osteoarthritis Cartilage. 2006, 14 (3): 250-257. 10.1016/j.joca.2005.10.001.CrossRefPubMed
6.
go back to reference Mandl EW, Jahr H, Koevoet JL, van Leeuwen JP, Weinans H, Verhaar JA, van Osch GJ: Fibroblast growth factor-2 in serum-free medium is a potent mitogen and reduces dedifferentiation of human ear chondrocytes in monolayer culture. Matrix Biol. 2004, 23 (4): 231-241. 10.1016/j.matbio.2004.06.004.CrossRefPubMed Mandl EW, Jahr H, Koevoet JL, van Leeuwen JP, Weinans H, Verhaar JA, van Osch GJ: Fibroblast growth factor-2 in serum-free medium is a potent mitogen and reduces dedifferentiation of human ear chondrocytes in monolayer culture. Matrix Biol. 2004, 23 (4): 231-241. 10.1016/j.matbio.2004.06.004.CrossRefPubMed
7.
go back to reference Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25 (4): 402-408. 10.1006/meth.2001.1262.CrossRefPubMed Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25 (4): 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
8.
go back to reference Orth MW, Peters TL, Hawkins JN: Inhibition of articular cartilage degradation by glucosamine-HCl and chondroitin sulphate. Equine Vet J Suppl. 2002, 224-229. 34 Orth MW, Peters TL, Hawkins JN: Inhibition of articular cartilage degradation by glucosamine-HCl and chondroitin sulphate. Equine Vet J Suppl. 2002, 224-229. 34
9.
go back to reference Dodge GR, Jimenez SA: Glucosamine sulfate modulates the levels of aggrecan and matrix metalloproteinase-3 synthesized by cultured human osteoarthritis articular chondrocytes. Osteoarthritis Cartilage. 2003, 11 (6): 424-432. 10.1016/S1063-4584(03)00052-9.CrossRefPubMed Dodge GR, Jimenez SA: Glucosamine sulfate modulates the levels of aggrecan and matrix metalloproteinase-3 synthesized by cultured human osteoarthritis articular chondrocytes. Osteoarthritis Cartilage. 2003, 11 (6): 424-432. 10.1016/S1063-4584(03)00052-9.CrossRefPubMed
10.
go back to reference Gouze JN, Bordji K, Gulberti S, Terlain B, Netter P, Magdalou J, Fournel-Gigleux S, Ouzzine M: Interleukin-1beta down-regulates the expression of glucuronosyltransferase I, a key enzyme priming glycosaminoglycan biosynthesis: influence of glucosamine on interleukin-1beta-mediated effects in rat chondrocytes. Arthritis Rheum. 2001, 44 (2): 351-360. 10.1002/1529-0131(200102)44:2<351::AID-ANR53>3.0.CO;2-M.CrossRefPubMed Gouze JN, Bordji K, Gulberti S, Terlain B, Netter P, Magdalou J, Fournel-Gigleux S, Ouzzine M: Interleukin-1beta down-regulates the expression of glucuronosyltransferase I, a key enzyme priming glycosaminoglycan biosynthesis: influence of glucosamine on interleukin-1beta-mediated effects in rat chondrocytes. Arthritis Rheum. 2001, 44 (2): 351-360. 10.1002/1529-0131(200102)44:2<351::AID-ANR53>3.0.CO;2-M.CrossRefPubMed
11.
go back to reference Sandy JD, Gamett D, Thompson V, Verscharen C: Chondrocyte-mediated catabolism of aggrecan: aggrecanase-dependent cleavage induced by interleukin-1 or retinoic acid can be inhibited by glucosamine. Biochem J. 1998, 335 (Pt 1): 59-66.CrossRefPubMedPubMedCentral Sandy JD, Gamett D, Thompson V, Verscharen C: Chondrocyte-mediated catabolism of aggrecan: aggrecanase-dependent cleavage induced by interleukin-1 or retinoic acid can be inhibited by glucosamine. Biochem J. 1998, 335 (Pt 1): 59-66.CrossRefPubMedPubMedCentral
12.
go back to reference Fenton JI, Chlebek-Brown KA, Caron JP, Orth MW: Effect of glucosamine on interleukin-1-conditioned articular cartilage. Equine Vet J Suppl. 2002, 219-223. 34 Fenton JI, Chlebek-Brown KA, Caron JP, Orth MW: Effect of glucosamine on interleukin-1-conditioned articular cartilage. Equine Vet J Suppl. 2002, 219-223. 34
13.
go back to reference Byron CR, Orth MW, Venta PJ, Lloyd JW, Caron JP: Influence of glucosamine on matrix metalloproteinase expression and activity in lipopolysaccharide-stimulated equine chondrocytes. Am J Vet Res. 2003, 64 (6): 666-671. 10.2460/ajvr.2003.64.666.CrossRefPubMed Byron CR, Orth MW, Venta PJ, Lloyd JW, Caron JP: Influence of glucosamine on matrix metalloproteinase expression and activity in lipopolysaccharide-stimulated equine chondrocytes. Am J Vet Res. 2003, 64 (6): 666-671. 10.2460/ajvr.2003.64.666.CrossRefPubMed
14.
go back to reference Bassleer C, Rovati L, Franchimont P: Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage. 1998, 6 (6): 427-434. 10.1053/joca.1998.0146.CrossRefPubMed Bassleer C, Rovati L, Franchimont P: Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage. 1998, 6 (6): 427-434. 10.1053/joca.1998.0146.CrossRefPubMed
15.
go back to reference Bassleer C, Henrotin Y, Franchimont P: In-vitro evaluation of drugs proposed as chondroprotective agents. Int J Tissue React. 1992, 14 (5): 231-241.PubMed Bassleer C, Henrotin Y, Franchimont P: In-vitro evaluation of drugs proposed as chondroprotective agents. Int J Tissue React. 1992, 14 (5): 231-241.PubMed
16.
go back to reference Lippiello L: Glucosamine and chondroitin sulfate: biological response modifiers of chondrocytes under simulated conditions of joint stress. Osteoarthritis Cartilage. 2003, 11 (5): 335-342. 10.1016/S1063-4584(03)00026-8.CrossRefPubMed Lippiello L: Glucosamine and chondroitin sulfate: biological response modifiers of chondrocytes under simulated conditions of joint stress. Osteoarthritis Cartilage. 2003, 11 (5): 335-342. 10.1016/S1063-4584(03)00026-8.CrossRefPubMed
17.
go back to reference Vidal y Plana RR, Bizzarri D, Rovati AL: Articular cartilage pharmacology: I. In vitro studies on glucosamine and non steroidal antiinflammatory drugs. Pharmacol Res Commun. 1978, 10 (6): 557-569. 10.1016/S0031-6989(78)80054-X.CrossRefPubMed Vidal y Plana RR, Bizzarri D, Rovati AL: Articular cartilage pharmacology: I. In vitro studies on glucosamine and non steroidal antiinflammatory drugs. Pharmacol Res Commun. 1978, 10 (6): 557-569. 10.1016/S0031-6989(78)80054-X.CrossRefPubMed
18.
go back to reference McCarty MF: Enhanced synovial production of hyaluronic acid may explain rapid clinical response to high-dose glucosamine in osteoarthritis. Med Hypotheses. 1998, 50 (6): 507-510. 10.1016/S0306-9877(98)90272-9.CrossRefPubMed McCarty MF: Enhanced synovial production of hyaluronic acid may explain rapid clinical response to high-dose glucosamine in osteoarthritis. Med Hypotheses. 1998, 50 (6): 507-510. 10.1016/S0306-9877(98)90272-9.CrossRefPubMed
19.
go back to reference McCarty MF, Russell AL, Seed MP: Sulfated glycosaminoglycans and glucosamine may synergize in promoting synovial hyaluronic acid synthesis. Med Hypotheses. 2000, 54 (5): 798-802. 10.1054/mehy.1999.0954.CrossRefPubMed McCarty MF, Russell AL, Seed MP: Sulfated glycosaminoglycans and glucosamine may synergize in promoting synovial hyaluronic acid synthesis. Med Hypotheses. 2000, 54 (5): 798-802. 10.1054/mehy.1999.0954.CrossRefPubMed
20.
go back to reference Uitterlinden EJ, Jahr H, Koevoet JL, Bierma-Zeinstra SM, Verhaar JA, Weinans H, van Osch GJ: Glucosamine reduces anabolic as well as catabolic processes in bovine chondrocytes cultured in alginate. Osteoarthritis Cartilage. 2007, 15 (11): 1267-1274. 10.1016/j.joca.2007.04.004.CrossRefPubMed Uitterlinden EJ, Jahr H, Koevoet JL, Bierma-Zeinstra SM, Verhaar JA, Weinans H, van Osch GJ: Glucosamine reduces anabolic as well as catabolic processes in bovine chondrocytes cultured in alginate. Osteoarthritis Cartilage. 2007, 15 (11): 1267-1274. 10.1016/j.joca.2007.04.004.CrossRefPubMed
21.
go back to reference Laurent TC, Fraser JR: Hyaluronan. Faseb J. 1992, 6 (7): 2397-2404.PubMed Laurent TC, Fraser JR: Hyaluronan. Faseb J. 1992, 6 (7): 2397-2404.PubMed
22.
go back to reference Laurent TC, Laurent UB, Fraser JR: The structure and function of hyaluronan: An overview. Immunol Cell Biol. 1996, 74 (2): A1-7. 10.1038/icb.1996.32.CrossRefPubMed Laurent TC, Laurent UB, Fraser JR: The structure and function of hyaluronan: An overview. Immunol Cell Biol. 1996, 74 (2): A1-7. 10.1038/icb.1996.32.CrossRefPubMed
23.
go back to reference Dahl LB, Dahl IM, Engstrom-Laurent A, Granath K: Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies. Ann Rheum Dis. 1985, 44 (12): 817-822. 10.1136/ard.44.12.817.CrossRefPubMedPubMedCentral Dahl LB, Dahl IM, Engstrom-Laurent A, Granath K: Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies. Ann Rheum Dis. 1985, 44 (12): 817-822. 10.1136/ard.44.12.817.CrossRefPubMedPubMedCentral
24.
go back to reference Fam H, Bryant JT, Kontopoulou M: Rheological properties of synovial fluids. Biorheology. 2007, 44 (2): 59-74.PubMed Fam H, Bryant JT, Kontopoulou M: Rheological properties of synovial fluids. Biorheology. 2007, 44 (2): 59-74.PubMed
25.
go back to reference Jiang D, Liang J, Noble PW: Hyaluronan in Tissue Injury and Repair. Annu Rev Cell Dev Biol . 2007, 23: 435-61. 10.1146/annurev.cellbio.23.090506.123337.CrossRefPubMed Jiang D, Liang J, Noble PW: Hyaluronan in Tissue Injury and Repair. Annu Rev Cell Dev Biol . 2007, 23: 435-61. 10.1146/annurev.cellbio.23.090506.123337.CrossRefPubMed
26.
go back to reference Wang CT, Lin YT, Chiang BL, Lin YH, Hou SM: 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. Osteoarthritis Cartilage. 2006, 14 (12): 1237-1247. 10.1016/j.joca.2006.05.009.CrossRefPubMed Wang CT, Lin YT, Chiang BL, Lin YH, Hou SM: 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. Osteoarthritis Cartilage. 2006, 14 (12): 1237-1247. 10.1016/j.joca.2006.05.009.CrossRefPubMed
28.
go back to reference Recklies AD, White C, Melching L, Roughley PJ: Differential regulation and expression of hyaluronan synthases in human articular chondrocytes, synovial cells and osteosarcoma cells. Biochem J. 2001, 354 (Pt 1): 17-24. 10.1042/0264-6021:3540017.CrossRefPubMedPubMedCentral Recklies AD, White C, Melching L, Roughley PJ: Differential regulation and expression of hyaluronan synthases in human articular chondrocytes, synovial cells and osteosarcoma cells. Biochem J. 2001, 354 (Pt 1): 17-24. 10.1042/0264-6021:3540017.CrossRefPubMedPubMedCentral
29.
go back to reference Persiani S, Rotini R, Trisolino G, Rovati LC, Locatelli M, Paganini D, Antonioli D, Roda A: Synovial and plasma glucosamine concentrations in osteoarthritic patients following oral crystalline glucosamine sulphate at therapeutic dose. Osteoarthritis Cartilage. 2007, 15 (7): 764-772. 10.1016/j.joca.2007.01.019.CrossRefPubMed Persiani S, Rotini R, Trisolino G, Rovati LC, Locatelli M, Paganini D, Antonioli D, Roda A: Synovial and plasma glucosamine concentrations in osteoarthritic patients following oral crystalline glucosamine sulphate at therapeutic dose. Osteoarthritis Cartilage. 2007, 15 (7): 764-772. 10.1016/j.joca.2007.01.019.CrossRefPubMed
30.
go back to reference Fenton JI, Chlebek-Brown KA, Peters TL, Caron JP, Orth MW: The effects of glucosamine derivatives on equine articular cartilage degradation in explant culture. Osteoarthritis Cartilage. 2000, 8 (6): 444-451. 10.1053/joca.1999.0320.CrossRefPubMed Fenton JI, Chlebek-Brown KA, Peters TL, Caron JP, Orth MW: The effects of glucosamine derivatives on equine articular cartilage degradation in explant culture. Osteoarthritis Cartilage. 2000, 8 (6): 444-451. 10.1053/joca.1999.0320.CrossRefPubMed
31.
go back to reference de Mattei M, Pellati A, Pasello M, de Terlizzi F, Massari L, Gemmati D, Caruso A: High doses of glucosamine-HCl have detrimental effects on bovine articular cartilage explants cultured in vitro. Osteoarthritis Cartilage. 2002, 10 (10): 816-825. 10.1053/joca.2002.0834.CrossRefPubMed de Mattei M, Pellati A, Pasello M, de Terlizzi F, Massari L, Gemmati D, Caruso A: High doses of glucosamine-HCl have detrimental effects on bovine articular cartilage explants cultured in vitro. Osteoarthritis Cartilage. 2002, 10 (10): 816-825. 10.1053/joca.2002.0834.CrossRefPubMed
32.
go back to reference Fenton JI, Chlebek-Brown KA, Peters TL, Caron JP, Orth MW: Glucosamine HCl reduces equine articular cartilage degradation in explant culture. Osteoarthritis Cartilage. 2000, 8 (4): 258-265. 10.1053/joca.1999.0299.CrossRefPubMed Fenton JI, Chlebek-Brown KA, Peters TL, Caron JP, Orth MW: Glucosamine HCl reduces equine articular cartilage degradation in explant culture. Osteoarthritis Cartilage. 2000, 8 (4): 258-265. 10.1053/joca.1999.0299.CrossRefPubMed
33.
go back to reference Gouze JN, Bianchi A, Becuwe P, Dauca M, Netter P, Magdalou J, Terlain B, Bordji K: Glucosamine modulates IL-1-induced activation of rat chondrocytes at a receptor level, and by inhibiting the NF-kappa B pathway. FEBS Lett. 2002, 510 (3): 166-170. 10.1016/S0014-5793(01)03255-0.CrossRefPubMed Gouze JN, Bianchi A, Becuwe P, Dauca M, Netter P, Magdalou J, Terlain B, Bordji K: Glucosamine modulates IL-1-induced activation of rat chondrocytes at a receptor level, and by inhibiting the NF-kappa B pathway. FEBS Lett. 2002, 510 (3): 166-170. 10.1016/S0014-5793(01)03255-0.CrossRefPubMed
34.
go back to reference Mello DM, Nielsen BD, Peters TL, Caron JP, Orth MW: Comparison of inhibitory effects of glucosamine and mannosamine on bovine articular cartilage degradation in vitro. Am J Vet Res. 2004, 65 (10): 1440-1445. 10.2460/ajvr.2004.65.1440.CrossRefPubMed Mello DM, Nielsen BD, Peters TL, Caron JP, Orth MW: Comparison of inhibitory effects of glucosamine and mannosamine on bovine articular cartilage degradation in vitro. Am J Vet Res. 2004, 65 (10): 1440-1445. 10.2460/ajvr.2004.65.1440.CrossRefPubMed
35.
go back to reference Mroz PJ, Silbert JE: Effects of [3H]glucosamine concentration on [3H]chondroitin sulphate formation by cultured chondrocytes. Biochem J. 2003, 376 (Pt 2): 511-515. 10.1042/BJ20030982.CrossRefPubMedPubMedCentral Mroz PJ, Silbert JE: Effects of [3H]glucosamine concentration on [3H]chondroitin sulphate formation by cultured chondrocytes. Biochem J. 2003, 376 (Pt 2): 511-515. 10.1042/BJ20030982.CrossRefPubMedPubMedCentral
36.
go back to reference Mroz PJ, Silbert JE: Use of (3)H-glucosamine and (35)S-sulfate with cultured human chondrocytes to determine the effect of glucosamine concentration on formation of chondroitin sulfate. Arthritis Rheum. 2004, 50 (11): 3574-3579. 10.1002/art.20609.CrossRefPubMed Mroz PJ, Silbert JE: Use of (3)H-glucosamine and (35)S-sulfate with cultured human chondrocytes to determine the effect of glucosamine concentration on formation of chondroitin sulfate. Arthritis Rheum. 2004, 50 (11): 3574-3579. 10.1002/art.20609.CrossRefPubMed
37.
go back to reference Laverty S, Sandy JD, Celeste C, Vachon P, Marier JF, Plaas AH: Synovial fluid levels and serum pharmacokinetics in a large animal model following treatment with oral glucosamine at clinically relevant doses. Arthritis Rheum. 2005, 52 (1): 181-191. 10.1002/art.20762.CrossRefPubMed Laverty S, Sandy JD, Celeste C, Vachon P, Marier JF, Plaas AH: Synovial fluid levels and serum pharmacokinetics in a large animal model following treatment with oral glucosamine at clinically relevant doses. Arthritis Rheum. 2005, 52 (1): 181-191. 10.1002/art.20762.CrossRefPubMed
Metadata
Title
Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants
Authors
EJ Uitterlinden
JLM Koevoet
CF Verkoelen
SMA Bierma-Zeinstra
H Jahr
H Weinans
JAN Verhaar
GJVM van Osch
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2008
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/1471-2474-9-120

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