High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity

Syndecan-1 is a heparan sulfate proteoglycan expressed on the surface of, a nd actively shed by, myeloma cells. Hepatocyte growth factor (HGF) is a cyt okine produced by myeloma cells. Previous studies have demonstrated elevate d levels of syndecan-1 and HGF in the serum of patients with myeloma, both of negative prognostic value for the disease. Here we show that the median concentrations of syndecan-1 (900 ng/mL) and HGF (6 ng/mL) in the marrow co mpartment of patients with myeloma are highly elevated compared with health y controls and controls with other diseases. We show that syndecan-1 isolat ed from the marrow of patients with myeloma seems to exist in an intact for m, with glucosaminoglycan chains. Because HGF is a heparan-sulfate binding cytokine, we examined whether it interacted with soluble syndecan-1, In sup ernatants from myeloma cells in culture as well as in pleural effusions fro m patients with myeloma, HGF existed in a complex with soluble syndecan-1, Washing myeloma cells with purified soluble syndecan-1 could effectively di splace HGF from the cell surface, suggesting that soluble syndecan-1 can ac t as a carrier for HGF in vivo. Finally, using a sensitive HGF bioassay (in terleukin-ii production from the osteosarcoma cell line Saos-2) and intact syndecan-1 isolated from the U-266 myeloma cell line, we found that the pre sence of high concentrations of syndecan-1 (more than 3 mug/mL) inhibited t he HGF effect, whereas lower concentrations potentiated it. HGF is only one of several heparin-binding cytokines associated with myeloma. These data i ndicate that soluble syndecan-1 may participate in the pathology of myeloma by modulating cytokine activity within the bone marrow. (C) 2000 by The Am erican Society of Hematology.