Hyaluronate inhibition of cell proliferation

Abstract

The proliferation of rabbit synovial cells, 3T3 cells, or simian virus-transformed 3T3 cells in cell culture was inhibited by the addition of hyaluronate to the culture medium. This effect was markedly dependent on the molecular weight and concentration of the hyaluronate. At the molecular weight and concentration of hyaluronate present in normal synovial fluid, proliferation was inhibited. At lower molecular weights or concentrations, as found in rheumatoid synovial fluid, hyaluronate was significantly less inhibitory. Thus, the changes in synovial fluid hyaluronate that are associated with arthropathies may contribute to a favorable environment for rheumatoid pannus expansion.The viscosity of synovial fluid from the rheumatoid joint is usually considerably less than that of normal synovial fluid, because of a decrease either in the degree of polymerization or in the concentration of hyaluronate (HA) in rheumatoid synovial fluid (1-4). A recent study suggests that the more important of these 2 factors is the decreased concentration of HA (4). Synovial cells, which are normally quiescent, are in constant contact with the HA of synovial fluid. In rheumatoid arthritis, these cells proliferate and con- In this study, we examined the effect of HA on proliferation of synovial and other cells in culture and found it to be inhibitory. However, our results indicate that the effect of HA on cell proliferation is markedly dependent on both the molecular weight and the concentration of HA in the cell culture medium. High molecular weight HA at high concentrations, as found in normal synovial fluid, is a potent inhibitor of cell division, whereas at lower molecular weights or at lower concentrations, as found in rheumatoid synovial fluid, it is less inhibitory and, in some cases, is even stimulatory . Therefore, alterations in either the concentration or the degree of polymerization of the HA of synovial fluid may contribute to the pathophysiology of rheumatoid arthritis by facilitating proliferation of the pannus. MATERIALS AND METHODSCells and culture procedures. Rabbit synovial fibroblast lines were obtained from Dr. C. Biswas (Tufts University School of Medicine, Boston, MA). These cells had been passaged in culture for approximately 2 years and had retained a constant morphology and the ability to produce large amounts of hyaluronate. The simian virus 40-transformed 3T3 (SV-3T3) and 3T3 cell lines were those used previously (5). All cells were maintained in Dulbecco's modified Eagle's medium (Gibco, Grand Island, NY) containing 10% fetal calf serum (Gibco), 100 units of penicillin per ml, 100 pg of streptomycin per ml, and 2.5 p g of fungizone per ml. The cells were grown and maintained in

Three Isoforms of Mammalian Hyaluronan Synthases Have Distinct Enzymatic Properties

“…Indeed, HA with high molecular weights at high concentrations inhibits cell growth, whereas HA with low molecular weights at low concentrations acts in the opposite manner (38,39). In addition, viscosity of the HA gel and the ability to hydrate large amounts of water were dependent on the molecular size of the HA chain.…”

Hyaluronan: fundamental principles and applications in cancer

“…HYA of high molecular mass (Ͼ1 ϫ 10 6 ) inhibited thymidine incorporation by 3T3 cells significantly at concentrations higher than 0.1 g L Ϫ1 , but HYA of low molecular mass was less inhibitory [42]. A series of experiments performed in our laboratory suggests that HYA could have some anti-proliferative activity through low-affinity interaction with growth factors.…”

Treatment of post-hematopoietic stem cell transplantation hemorrhagic cystitis with intravesicular sodium hyaluronate

“…Sodium hyaluronate has many biological activities, which include inhibition of immune complexes, adherence to polymorphonuclear cells, inhibition of leukocyte migration, regulation of fibroblast and endothelial cell proliferation, enhancement of connective tissue healing, etc. 31 Based on the different mechanisms of action of sodium hyaluronate, and the known efficacy in the setting of interstitial cystitis, we decided to test the efficacy of a similar approach in patients with post-transplant HC.…”