Sulfated glycosaminoglycans and glucosamine may synergize in promoting synovial hyaluronic acid synthesis

doi:10.1054/mehy.1999.0954

Medical Hypotheses

Volume 54, Issue 5, May 2000, Pages 798-802

https://doi.org/10.1054/mehy.1999.0954 Get rights and content

Abstract

High-molecular-weight hyaluronic acid (HA) produced by the synovium may function physiologically to aid preservation of cartilage structure and prevent arthritic pain; both the size and concentration of HA in synovial fluid are diminished in osteoarthritis (OA). Glucosamine therapy for OA can be expected to increase synovial HA production by providing rate-limiting substrate. In addition, certain sulfated glycosaminoglycans and polysaccharides – including chondroitin sulfate (CS), dermatan sulfate, and pentosan polysulfate – stimulate synovial HA production, apparently owing to a hormone-like effect triggered by the binding of these polymers to membrane proteins of synovial cells. Surprisingly, a significant proportion of orally administered CS is absorbed as intact polymers – apparently by pinocytosis. These considerations may rationalize clinical studies concluding that oral CS provides slow-onset but durable pain relief and functional improvement in OA. The possibility that oral glucosamine and CS may interact in a complementary or synergistic fashion to improve synovial fluid HA content in OA should be assessed in clinical studies, and the potential of adjunctive CS administration to improve the clinical response achievable with optimal intakes of glucosamine should likewise be evaluated. In light of the fact that the synovium virtually functions as a ‘placenta’ for cartilage, focusing on synovium as the target for therapeutic intervention in OA may be a rational strategy.

References (49)

M.F. McCarty
Enhanced synovial production of hyaluronic acid may explain rapid clinical response to high-dose glucosamine in osteoarthritis
Med Hypotheses
(1998)
J.J. Kim et al.
Effect of D-glucosamine concentration on the kinetics of muco-polysaccharide biosynthesis in cultured chick embryo vertebral cartilage
J Biol Chem
(1974)
R.R. Vidal y Plana et al.
Articular cartilage pharmacology, I: In vitro studies on glucosamine and non steroidal antiinflammatory drugs
Pharmacol Res Commun
(1978)
H. Nishikawa et al.
Influences of sulfated glycosaminoglycans on biosynthesis of hyaluronic acid in rabbit knee synovial membrane
Arch Biochem Biophys
(1985)
H. Nishikawa et al.
Glycosaminoglycan polysulfate-induced stimulation of hyaluronic acid synthesis in rabbit knee synovial membrane: involvement of binding protein and calcium ion
Arch Biochem Biophys
(1988)
P.M. Hanno
Analysis of long-term elmiron therapy for interstitial cysitis
Urology
(1997)
N.E. Larsen et al.
Effect of hylan on cartilage and chondrocyte cultures
J Orthop Res
(1992)
K. Fukuda et al.
Hyaluronic acid increases proteoglycan synthesis in bovine articular cartilage in the presence of interleukin-1
J Pharmacol Exp Ther
(1996)
T. Yasui et al.
Effects of hyaluronan on the production of stromelysin and tissue inhibitor of metalloproteinase-1 (TIMP-1) in bovine articular chondrocytes
Biomedical Research
(1992)
K. Karzel et al.
Effects of hexosamine derivatives and uronic acid derivatives on glycosaminoglycane metabolism of fibroblast cultures
Pharmacology
(1971)

S. Mitsuyama et al.

Effects of glycosaminoglycan polysulfate on extracellular matrix metabolism in human skin cells

Res Commun Mol Pathol Pharmacol

(1994)

J.J. Brennan et al.

Effects of glycosaminoglycan polysulfate treatment on soundness, hyaluronic acid content of synovial fluid and proteoglycan aggregate in articular cartilage of lame boars

Can J Vet Res

(1987)

D.J. Francis et al.

Pentosan polysulphate and glycosaminoglycan polysulphate stimulate the synthesis of hyaluronan in vivo

Rheumatol Int

(1993)

P. Kongtawelert et al.

Pentosan polysulfate (Cartrophen) prevents the hydrocortisone induced loss of hyaluronic acid and proteoglycans from cartilage of rabbit joints as well as normalizes the keratan sulfate levels in their serum

J Rheumatol

(1989)

G. Verbruggen et al.

Intra-articular injection pentosanpolysulphate results in increased hyaluronan molecular weight in joint fluid

Clin Exp Rheumatol

(1992)

E.A. Balazs et al.

Hyaluronic acid in synovial fluid, I: Molecular parameters of hyaluronic acid in normal and arthritic human fluids

Arthritis Rheum

(1967)

E. Vuorio et al.

Synthesis of undepolymerised hyaluronic acid by fibroblasts cultured from rheumatoid and non-rheumatoid synovitis

Rheumatology

(1982)

L.B. Dahl et al.

Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies

Ann Rheum Dis

(1985)

J. Vacha et al.

Effect of glycosaminoglycan polysulphate on the metabolism of cartilage ribonucleic acid

Arzneimittelforschung

(1984)

A. Knänfelt

Synthesis of articular cartilage proteoglycans by isolated bovine chondrocytes

Agents Actions

(1984)

A. Conte et al.

Metabolic fate of partially depolymerized chondroitin sulfate administered to the rat

Drugs Exp Clin Res

(1991)

L. Palmieri et al.

Metabolic fate of exogenous chondroitin sulfate in the experimental animal

Arzneimittelforschung

(1990)

A. Conte et al.

Metabolic fate of exogenous chondroitin sulfate in man

Arzneimittelforschung

(1991)

G. Ronca et al.

Metabolic fate of partially depolymerized shark chondroitin sulfate in man

International Journal of Clinical Pharmacological Research

(1993)

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Among these, ECM not only guides the tissue development but also drives cell fate [25]. Chondroitin sulfate (CS), a member of glycosaminoglycan (GAG) family, is a major type of ECM primarily found in cartilage, bone, and skin [26,27]. CS is capable of regulating cartilage formation [28].
3D electrospun nanofibrous scaffolds have been developed for cartilage regeneration, however, there is no consensus on the preferable method for biocompatible scaffolds that enhance regeneration and attenuate inflammation. We designed a 3D porous electrospun polylactic acid (PLA) @gelatin-based scaffold by a novel method. Chondroitin sulfate (CS), commonly used in clinical cartilage treatment, is capable of regulating cartilage formation and inhibiting inflammation. Thus we further functionalized the 3D scaffold by crosslinking of CS, assuming that CS-functionalized scaffold (CSS) would promote cartilage regeneration and modulate inflammation. We confirmed that CSS exhibits not only appropriate reversible compressibility and mechanical property, but also appropriate biocompatibility, allowing cell proliferation. In vitro, the potential of CSS for chondrogenic differentiation was improved compared to control and PLA@gelatin scaffold as chondrogenic markers Collagen2 and Aggrecan was significantly increased. Meanwhile, significant reduction in two crucial inflammatory factors (NO and PGE2) in CSS group demonstrated inflammation inhibition. In vivo, rabbit cartilage defects were created and CSS effectively promoted cartilage repair. Additionally, superior anti-inflammation effect of CSS was demonstrated by reduction in iNOS and PGES, enzymes producing NO and PGE2, respectively by immunohistology. Our results indicated the preferable property of CSS for cartilage regeneration and its potential in immunoregulation.
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The major application for CS is as anti-inflammatory drug for treating osteoarthritis and has been recommended by European League against Rheumatism as a symptomatic slow acting drug for knee and hand osteoarthritis treatment (Michel et al., 2002; Volpi, 2009). CS inhibits cartilage degradative enzymes and its chondroprotective properties may enhance the biosynthesis of connective tissue and increase the synovial fluid viscosity at disease sites (Belcher et al., 1997; McCarty et al., 2000). Clinical studies suggest that CS treatment relieves pain and stiffness caused by arthritis with minor side effects such as increasing intestinal gases and stool softening (Schiraldi et al., 2010).
Chondroitin sulfates, widely used in the treatment of arthritis, are glycosaminoglycans extracted from food animal tissues. As part of our ongoing efforts to separate the food chain from the drug chain, we are examining the possibility of using metabolic engineering to produce chondroitin sulfate in Escherichia coli. Chondroitin is a valuable precursor in the synthesis of chondroitin sulfate. This study proposes a safer and more feasible approach to metabolically engineer chondroitin production by expressing genes from the pathogenic E. coli K4 strain, which natively produces a capsular polysaccharide that shares the similar structure with chondroitin, into the non-pathogenic E. coli BL21 Star™ (DE3) strain. The ePathBrick vectors, allowing for multiple gene addition and expression regulatory signal control, are used for metabolic balancing needed to obtain the maximum potential yield. The resulting engineered strain produced chondroitin, as demonstrated by ¹H NMR and disaccharide analysis, relying on chondrotinase treatment followed by liquid chromatography–mass spectrometry. The highest yield from shake flask experiment was 213 mg/L and further increased to 2.4 g/L in dissolved oxygen-stat fed batch bioreactor.
Synthesis and optimization of hyaluronic acid-methotrexate conjugates to maximize benefit in the treatment of osteoarthritis
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We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA–MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like synoviocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis.
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Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA–MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA–MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis.
Chondroitin sulfate intake inhibits the IgE-mediated allergic response by down-regulating Th2 responses in mice
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Chondroitin sulfate (CS) was administered orally to BALB/c mice immunized intraperitoneally with ovalbumin (OVA) and/or dinitrophenylated OVA. The titers of antigen-specific IgE and IgG1 in mouse sera were determined. The antigen-specific IgE production by mice fed ad libitum with CS was significantly inhibited. We also examined the effect of feeding CS on immediate-type hypersensitivity. One hour after antigen stimulation, the ears of mice fed with CS swelled less than those of the control mice. Furthermore, the rise in serum histamine in the mice fed with CS under active systemic anaphylaxis was significantly lower than that in the controls. We next examined the pattern of cytokine production by splenocytes from mice followed by re-stimulation with OVA in vitro. The splenocytes from the mice fed with CS produced less interleukin (IL)-5, IL-10, and IL-13 than those from the control group. In contrast, the production of interferon-γ and IL-2 by the splenocytes of mice fed with CS was not significantly different from those in the control mice. In addition, the production of transforming growth factor-β from the splenocytes of mice fed with CS was significantly higher than that of the control mice. Furthermore, we showed that the percentages of CD4⁺ cells, CD8⁺ cells, and CD4⁺CD25⁺ cells in the splenocytes of mice fed with CS are significantly higher than those of the control. These findings suggest that oral intake of CS inhibits the specific IgE production and antigen-induced anaphylactic response by up-regulating regulatory T-cell differentiation, followed by down-regulating the Th2 response.
Structural Effects of Radiation Sterilisation on Sodium Hyaluronate
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The molecular weight profiles, reducing and unsaturated carbohydrates in gamma and electron beam (E-beam) irradiated (0-100 kGys) sodium hyaluronate samples (NaHA, in solid form and 1% w/v aqueous solutions), were determined by gel permeation chromatography (GPC), 3,5-dintrosalicylic (DNS) acid assay, and Warren assay, respectively, in order to assess induced degradation, the latter via an anticipated free radical-induced β-elimination mechanism. NaHA was depolymerised by both gamma- and E-beam-irradiation, the extent of depolymerisation being dependent upon irradiation intensity. Gamma-irradiation generally resulted in higher degrees of depolymerisation than E-beam-irradiation, and NaHA solutions were depolymerised to a greater extent than NaHA solids by gamma-irradiation, at the same irradiation levels. Measured reducing sugars correlated with theoretical levels (calculated from determined peak molecular weights, Mp). Measured non-reducing unsaturated glucuronates were lower than measured / theoretical reducing sugars, indicating that not all non-reducing ends created by depolymerisation contained Warren assay active unsaturated sugars.

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Regular ArticleSulfated glycosaminoglycans and glucosamine may synergize in promoting synovial hyaluronic acid synthesis

Abstract

Med Hypotheses

J Biol Chem

Pharmacol Res Commun

Arch Biochem Biophys

Arch Biochem Biophys

Urology

Effect of hylan on cartilage and chondrocyte cultures

J Orthop Res

Hyaluronic acid increases proteoglycan synthesis in bovine articular cartilage in the presence of interleukin-1

J Pharmacol Exp Ther

Effects of hyaluronan on the production of stromelysin and tissue inhibitor of metalloproteinase-1 (TIMP-1) in bovine articular chondrocytes

Biomedical Research

Effects of hexosamine derivatives and uronic acid derivatives on glycosaminoglycane metabolism of fibroblast cultures

Pharmacology

Effects of glycosaminoglycan polysulfate on extracellular matrix metabolism in human skin cells

Res Commun Mol Pathol Pharmacol

Effects of glycosaminoglycan polysulfate treatment on soundness, hyaluronic acid content of synovial fluid and proteoglycan aggregate in articular cartilage of lame boars

Can J Vet Res

Pentosan polysulphate and glycosaminoglycan polysulphate stimulate the synthesis of hyaluronan in vivo

Rheumatol Int

Pentosan polysulfate (Cartrophen) prevents the hydrocortisone induced loss of hyaluronic acid and proteoglycans from cartilage of rabbit joints as well as normalizes the keratan sulfate levels in their serum

J Rheumatol

Intra-articular injection pentosanpolysulphate results in increased hyaluronan molecular weight in joint fluid

Clin Exp Rheumatol

Hyaluronic acid in synovial fluid, I: Molecular parameters of hyaluronic acid in normal and arthritic human fluids

Arthritis Rheum

Synthesis of undepolymerised hyaluronic acid by fibroblasts cultured from rheumatoid and non-rheumatoid synovitis

Rheumatology

Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies

Ann Rheum Dis

Effect of glycosaminoglycan polysulphate on the metabolism of cartilage ribonucleic acid

Arzneimittelforschung

Synthesis of articular cartilage proteoglycans by isolated bovine chondrocytes

Agents Actions

Metabolic fate of partially depolymerized chondroitin sulfate administered to the rat

Drugs Exp Clin Res

Metabolic fate of exogenous chondroitin sulfate in the experimental animal

Arzneimittelforschung

Metabolic fate of exogenous chondroitin sulfate in man

Arzneimittelforschung

Metabolic fate of partially depolymerized shark chondroitin sulfate in man

International Journal of Clinical Pharmacological Research

Regular Article
Sulfated glycosaminoglycans and glucosamine may synergize in promoting synovial hyaluronic acid synthesis