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Syndecan-1 Is a Multifunctional Regulator of Myeloma Pathobiology:
Control of Tumor Cell Survival, Growth, and Bone Cell Differentiation
Madhav V. Dhodapkar,
Etsuko Abe,
Allison Theus,
Marie Lacy,
J.
Kevin Langford,
Bart Barlogie, and
Ralph D. Sanderson
From the Divisions of Hematology-Oncology and Endocrinology and the
Departments of Pathology and Anatomy, University of Arkansas for
Medical Sciences and VA Medical Center, Little Rock, AR.
Multiple myeloma is characterized by an accumulation of malignant
plasma cells in the bone marrow coupled with an altered balance of
osteoclasts and osteoblasts, leading to lytic bone disease. Although
some of the cytokines driving this process have been characterized,
little is known about the negative regulators. We show that syndecan-1
(CD 138), a heparan sulfate proteoglycan, expressed on and actively
shed from the surface of most myeloma cells, induces apoptosis and
inhibits the growth of myeloma tumor cells and also mediates decreased
osteoclast and increased osteoblast differentiation. The addition of
intact purified syndecan-1 ectodomain (1 to 6 nmol/L) to myeloma cell
lines in culture leads to induction of apoptosis and dose-dependent
growth inhibition, with concurrent downregulation of cyclin D1. The
addition of purified syndecan-1 in picomolar concentrations to bone
marrow cells in culture leads to a dose-dependent decrease in
osteoclastogenesis and a smaller increase in osteoblastogenesis. In
contrast to the effect on myeloma cells, the effect of syndecan-1 on
osteoclastogenesis only requires the syndecan-1 heparan sulfate chains
and not the intact ectodomain, suggesting that syndecan's effect on
myeloma and bone cells occurs through different mechanisms. When
injected in severe combined immune deficient (scid) mice,
control-transfected myeloma cells (ARH-77 cells) expressing little
syndecan-1 readily form tumors, leading to hind limb paralysis and
lytic bone disease. However, after the injection of
syndecan-1-transfected ARH-77 cells, the development of
disease-related morbidity and lytic bone disease is significantly
inhibited. Taken together, our data demonstrate, both in vitro and in
vivo, that syndecan-1 has a significant beneficial effect on the
behavior of both myeloma and bone cells and therefore may represent one
of the central molecules in the regulation of myeloma pathobiology.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2679-2688
© 1998 by The American Society of Hematology.
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