Abstract
A major cause of morbidity in patients with multiple myeloma is the development and progression of bone disease. Myeloma bone disease is characterized by rampant osteolysis in the presence of absent or diminished bone formation. Heparanase, an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate chains, is upregulated in a variety of human cancers including multiple myeloma. We and others have shown that heparanase enhances osteoclastogenesis and bone loss. However, increased osteolysis is only one element of the spectrum of myeloma bone disease. In the present study, we hypothesized that heparanase would also affect mesenchymal cells in the bone microenvironment and investigated the effect of heparanase on the differentiation of osteoblast/stromal lineage cells. Using a combination of molecular, biochemical, cellular and in vivo approaches, we demonstrated that heparanase significantly inhibited osteoblast differentiation and mineralization, and reduced bone formation in vivo. In addition, heparanase shifts the differentiation potential of osteoblast progenitors from osteoblastogenesis to adipogenesis. Mechanistically, this shift in cell fate is due, at least in part, to heparanase-enhanced production and secretion of the Wnt signaling pathway inhibitor DKK1 by both osteoblast progenitors and myeloma cells. Collectively, these data provide important new insights into the role of heparanase in all aspects of myeloma bone disease and strongly support the use of heparanase inhibitors in the treatment of multiple myeloma.
Highlights
Multiple myeloma (MM) is a hematologic malignancy characterized by the development of progressive and destructive osteolytic bone disease that is associated with diminished numbers of marrow stromal cells and osteoblasts [17, 27]
To determine the effects of heparanase expression by myeloma cells on mesenchymal lineage cells, we first examined the effect of heparanase on osteoblastogenesis and parameters of bone formation by evaluating osteoblast parameters in SCID-hu mice [36]
The results presented here demonstrate that heparanase expression by myeloma cells can alter the fate of osteoblast progenitor cells, directing cellular differentiation toward adipocytes rather than osteoblasts
Summary
Multiple myeloma (MM) is a hematologic malignancy characterized by the development of progressive and destructive osteolytic bone disease that is associated with diminished numbers of marrow stromal cells and osteoblasts [17, 27]. Despite recent advances in treatment strategies myeloma remains largely incurable, with renal failure and immunosuppression as well as bone destruction the major causes of morbidity [11, 14, 27]. We have demonstrated that increased levels of heparanase dramatically enhance myeloma tumor growth, angiogenesis, and the spontaneous metastasis of tumor cells to bone [18, 26, 33, 35]. We reported that the expression of heparanase by myeloma cells markedly increased local and systemic osteolysis [36]
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