Enhanced synovial production of hyaluronic acid may explain rapid clinical response to high-dose glucosamine in osteoarthritis

doi:10.1016/S0306-9877(98)90272-9

Medical Hypotheses

Volume 50, Issue 6, June 1998, Pages 507-510

https://doi.org/10.1016/S0306-9877(98)90272-9 Get rights and content

Abstract

Anecdotal reports of rapid symptomatic response to high-dose glucosamine in osteoarthritis are not credibly explained by the traditional view that glucosamine promotes synthesis of cartilage proteoglycans. An alternative or additional possibility is that glucosamine stimulates synovial production of hyaluronic acid (HA), which is primarily responsible for the lubricating and shock-absorbing properties of synovial fluid. Many clinical and veterinary studies have shown that intra-articular injections of high-molecular-weight HA produce rapid pain relief and improved mobility in osteoarthritis. HA has anti-inflammatory and analgesic properties, and promotes anabolic behavior in chondrocytes. The concentration and molecular weight of synovial fluid HA are decreased in osteoarthritis; by reversing this abnormality, high-dose glucosamine may provide rapid symptomatic benefit, and in the longer term aid the repair of damaged cartilage.

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Osteoarthritis is a common and debilitating joint disease that primarily affects the knee and hip joints, resulting in a significant loss of articular cartilage. While non-steroidal anti-inflammatory drugs are often used to treat pain in osteoarthritis, they are not a suitable long-term solution because of their associated adverse events. Slow-acting symptom-modifying or structure/disease-modifying osteoarthritis drugs have demonstrated safety with minimal side effects, but their efficacy remains controversial. We hypothesize that differences in physical activity patterns among patients with knee or hip osteoarthritis could partly explain the large heterogeneity in response to oral glucosamine/chondroitin. Our hypothesis suggests that stagnant synovial fluid may restrict the diffusion of these drugs into the joint cartilage cells, leading to variable clinical outcomes. In this study, we provide evidence to support this hypothesis and propose a simple post-intake physical therapy procedure to enhance the effectiveness of chondroprotective agents. If validated, this approach could be a valuable addition to non-operative osteoarthritis management, potentially resulting in remarkable improvements in patient outcomes.
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Also, the additional desired properties of glucosamine has been investigated; glucosamine is known to stimulate the synovial production of hyaluronic acid (HA), which is mainly responsible for the lubrication and shock-absorbing properties of synovial fluid. HA has also anti-inflammatory and analgesic properties, and promotes anabolic behavior in chondrocytes (McCarty, 1998). The sustained drug release properties for the GA2 formulation is expected to extend the localized pharmacological activity of the nanosystem by increasing the local retention of indomethacin within the injected joints.
Osteoarthritis is a propagated debilitating condition affecting patients' quality of life. Intra-articular injection approach was investigated as a localized treatment strategy providing: site-specific delivery, decreased side effects and, increased patient compliance. A 3² full factorial experimental design was employed to prepare the indomethacin-loaded self-assembling nanosystems (SANS). The surfactant (Poloxamer 407/Tetronic 90R4) ratio and the poly(lactic-co-glycolic acid) (PLGA) concentration significantly affected encapsulation efficiency and drug release (p < 0.05). The optimized formula was subjected to modification by addition of different proteoglycans, as a compensatory treatment, to improve its pharmacological properties. The modified SANS, containing glucosamine (150 mg), was selected for in-vivo studies as it had a sustained drug release profile and a small particle size (173.90 nm). The effect of the optimized SANS, with or without PLGA, was compared with the modified formula containing glucosamine and, with the drug suspension on the arthritic knee joints of rats. It was found that the formulation containing PLGA and glucosamine showed significantly higher reduction in both, knee diameter and TNF-α levels, compared to other groups. Furthermore, all SANS showed histological improvement in the cellularity of the synovial membranes and joints. Our results indicate that SANS containing PLGA and glucosamine is capable of treating arthritic joints.
Conservative treatment of asymmetric ankle osteoarthritis
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Glucosamine and chondroitin are the 2 supplementations that claim to have an affect on OA. Glucosamine is believed to restore and repair the extracellular matrix by acting as a substrate for the formation of chondroitin sulfate and to stimulate the synovial production of hyaluronic acid.1 Chondroitin sulfate seems to also initiate synovial fabrication of hyaluronic acid.2
Dietary and Viscosupplementation in Ankle Arthritis
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Glucosamine is thought to have its effects by inhibiting the production of interleukin-1-stimulated, proinflammatory mediators such as prostaglandin E2, nitric oxide, NFκβ, and matrix metalloproteinase 1 [10]. One other possibility is that glucosamine may increase production of hyaluronic acid [11]. Chondroitin sulfate may also have a variety of effects, including inhibition of leukocyte elastase, tissue elastase, and the migration of polymorphonuclear leukocytes.
Glucosamine and chondroitin sulfate are the most well-marketed dietary supplements directed toward managing symptoms associated with osteoarthritis. The presumption of their benefit in the ankle is based largely on promising results from their use in knee osteoarthritis. Likewise, viscosupplementation has proved to be efficacious in the management of osteoarthritis of the knee. Preliminary studies demonstrate a realization of this benefit in the ankle joint, but further research is required. So far, the literature has shown the dietary and viscosupplementation discussed in this article to be relatively safe for use.
Glucosamine sulphate. From condromodulation to symptomatic reduction and progression of osteoarthritis
2006, Seminarios de la Fundacion Espanola de Reumatologia
La artrosis es una de las causas más frecuentes de dolor y discapacidad en las personas mayores. Dado el aumento de la población anciana, cada vez más se precisan de intervenciones terapéuticas que permitan retrasar sus deletéreos efectos en la salud de las personas. Por consiguiente, una política sanitaria responsable debería tener en cuenta esta demanda social y un enfoque prioritario de recursos para esta enfermedad cada vez más prevalente. El interés clínico e investigador por esta afección se ha renovado. El mayor conocimiento fisiopatológico de los cambios inmunológicos y enzimáticos que operan en la enfermedad ha modificado el concepto mecanicista que se tenía de su patogenia incorporando otro más dinámico y biológico, en que el condrocito desempeña un papel fundamental, y además sería sensible al tratamiento farmacológico, lo que retrasaría el proceso degenerativo. El sulfato de glucosamina (SG) es una molécula con un amplio abanico de acciones biológicas entre las que sobresalen la antiinflamatoria y la reguladora al alza del metabolismo de la matriz del cartílago. Recientes estudios in vitro demuestran este perfil condromodulador que favorece el anabolismo del condrocito. Igualmente, estudios a largo plazo, aleatorizados y controlados con placebo han mostrado una mejora en los síntomas y de la progresión del estrechamiento articular en personas tratadas con SG, junto con un perfil de seguridad similar al de los grupos placebo. El siguiente artículo realiza un acercamiento al control de la enfermedad con los fármacos sintomáticos de acción lenta y modificadores de la estructura en la artrosis y revisa las evidencias disponibles del SG en el tratamiento específico de la artrosis.
Osteoarthritis (OA) is one of the most frequent causes of pain and disability in the elderly. Given the old population's increase, therapeutic interventions are necessary to allow retarding the deleterious effects on the health of people. Consequently, a responsible sanitary policy should keep in mind this social demand and a high-priority focus of resources for this prevalent disease. There is now a renewed clinical and research interest in this complaint. Greather physiopathological understanding of the immunological and enzymatic changes that influence the disease have modified the mechanical concept once held of its pathogenicity to include other more dynamic and biological causes in which plays a basic role. Furthermore, it would also be sensitive to pharmacological treatment, thus delaying the degenerative process. Glucosamine sulphate (GS) is a molecule with a wide range of biological actions with some of the most important being the antiinflammatory effect and an increased metabolism of the cartilage matrix. Recent studies in vitro show a profile of chondro-modulation that favors the anabolism of the chondrocyte. Similarly, long-term, prospective, placebo-controlled studies have shown an improvement in the symptoms and of the progression of the narrowing of the articular space in people treated with GS, with a profile of similar safety to the placebo groups. The following article carries out an approach to the control of the illness with the Delayed-acting symptomatic drugs and disease modyfing drugs in the OA and it reviews the available evidences of GS in the specific treatment of OA.
TSG-6 and calcium ions are essential for the coupling of inter-alpha-trypsin inhibitor to hyaluronan in human synovial fluid
2004, Osteoarthritis and Cartilage
Objective: To investigate the role of tumor necrosis factor stimulated gene 6 (TSG-6) and metal ions in the coupling of inter-α-trypsin inhibitor (ITI) to hyaluronan in human synovial fluid.
Design: The concentration of ITI heavy chains bound to hyaluronan was determined by a two-step electrophoretic technique. Synovial fluid, TSG-6 depleted synovial fluid and metal chelated synovial fluid were tested for their ability to support the coupling of ITI heavy chains to hyaluronan.
Results: When synovial fluid was mixed with an ITI-source (serum or purified ITI), coupling of ITI heavy chains to hyaluronan took place. TSG-6 immunodepleated synovial fluid lost the coupling activity, but addition of recombinant TSG-6 restored the activity. EDTA inhibited the coupling activity, but combinations of the metal-ion chelators Mg-EGTA and Ca-EGTA demonstrated, that Ca⁺⁺is essential for the coupling of ITI heavy chains to hyaluronan.
Conclusions: Tumor necrosis factor stimulated gene 6 (TSG-6) and calcium ions are both essential for the coupling of inter-α-trypsin inhibitor to hyaluronan in human synovial fluid.

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Enhanced synovial production of hyaluronic acid may explain rapid clinical response to high-dose glucosamine in osteoarthritis

Abstract

Med Hypotheses

Semin Arthritis Rheum

Semin Arthritis Rheum

Semin Arthritis Rheum

J Biol Chem

Pharmacol Res Commun

Med Hypotheses

The physical properties of synovial fluid and the special role of hyaluronic acid

The role of hyaluronic acid (hyaluronan) in health and disease: interactions with cells, cartilage and components of synovial fluid

Clin Exp Rheumatol

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

Arthritis Rheum

Synthesis of underpolymerised 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

Preliminary clinical assessment of sodium hyaluronate injection into human arthritic joints

Pathol Biol

Intraarticular hyaluronan injections in the treatment of osteoarthritis: state-of-the-art review

J Rheumatol

Hyaluronic acid: a review of its pharmacology and use as a surgical aid in ophthalmology, and its therapeutic potential in joint disease and wound healing

Drugs

Intra-articular hyaluronate (HA) reduces keratan sulfate levels in osteoarthritic synovial fluid (OA)

Arthritis Rheum

The effects of intraarticular hyaluronan on cartilage and subchondral bone changes in an ovine model of early osteoarthritis

J Rheumatol

Hyaluronic acid (hyaluronan) in experimental osteoarthritis

J Rheumatol

Intmarticular sodium hyaluronate injections in the Pond-Nuki experimental model of osteoarthritis in dogs, 11: Morphological findings

Clin Orthop

Effect of hylan on cartilage and chondrocyte cultures

J Orthop Res