aranase Enhances Local and Systemic Osteolysis in tiple Myeloma by Upregulating the Expression and R retion of RANKL

Downlo essive bone destruction is a major cause of morbidity in myeloma patients. However, the biological nisms involved in the pathogenesis of myeloma-induced bone disease are not fully understood. Heparan enzyme that cleaves the heparan sulfate chains of proteoglycans, is upregulated in a variety of huumors, including multiple myeloma. We previously showed that heparanase promotes robust myeloma growth and supports spontaneous metastasis of tumor cells to bone. In the present study, we show, for st time, that the expression of heparanase by myeloma tumor cells remarkably enhances bone destruccally within the tumor microenvironment. In addition, enhanced heparanase expression in the primary also stimulated systemic osteoclastogenesis and osteolysis, thus mimicking the systemic osteoporosis seen in myeloma patients. These effects occur, at least in part, as the result of a significant elevation in pression and secretion of receptor activator of NF-κB ligand (RANKL) by heparanase-expressing myeells. Moreover, analysis of bone marrow biopsies from myeloma patients reveals a positive correlation en the level of expression of heparanase and RANKL. Together, these discoveries reveal a novel and key betwe role for heparanase in promoting tumor osteolysis and show that RANKL is central to the mechanism of heparanase-mediated osteolysis in myeloma. Cancer Res; 70(21); 8329–38. ©2010 AACR.