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Myeloma cells upregulate interleukin-6 secretion in osteoblastic cells
through cell-to-cell contact but downregulate osteocalcin
S Barille, M Collette, R Bataille and M Amiot
Laboratoire d'Oncogenese Immunohematologique and Inserm U211, Institut de
Biologie, Nantes, France.
Previous studies have shown that bone marrow, especially the bone
microenvironment, may play an important role in the pathogenesis of
multiple myeloma (MM). To elucidate the relationship between myeloma cells
and bone cells, mainly osteoblasts, we have established a coculture system
between two interleukin-6 (IL-6)-dependent myeloma cell lines, XG1 and XG6,
and the osteosarcoma cell lines Saos-2 and MG63. Both osteosarcoma cell
lines have retained major functions of normal osteoblasts; principally, the
capacity to produce hematopoietic growth factors (including IL-6) and
osteocalcin, a noncollagenic protein essential in the bone formation
process. Because IL-6 is a critical growth factor in MM, we have examined
the IL-6 osteoblastic cell production in our coculture system. XG1 cells
strongly upregulate IL-6 production by MG63 and Saos-2 cells. Of major
interest, the triggering of IL-6 is totally dependent on the physical
contact between myeloma cells and osteoblastic cells, contact that is
partly mediated by CD44, CD56, and fibronectin interactions. Osteocalcin
production by MG63 and Saos-2 cells has previously been shown to be
dependent on 1,25- (OH)2D3. We demonstrate that XG1 and XG6 cells reduced
the amount of osteocalcin in MG63 coculture cell supernatants, a reduction
that is partly mediated by a soluble factor and by cell-to-cell contact.
Notably, whereas one of the myeloma cell lines, XG6, has lost its capacity
to stimulate IL-6 production by osteoblastic cell lines, both XG1 and XG6
cell lines remain able to reduce the osteocalcin amount, indicating that
IL-6 and osteocalcin levels are regulated by two different pathways. In
conclusion, these data strongly support the concept that the bone
microenvironment is directly modified by contact with myeloma cells and are
consistent with the characteristics observed in vivo in patients with MM
patients, ie, abnormally high IL-6 and low osteocalcin levels,
respectively.
Volume 86,
Issue 8,
pp. 3151-3159,
10/15/1995
Copyright © 1995 by The American Society of Hematology
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