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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-04-1121.
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Blood, 15 December 2002, Vol. 100, No. 13, pp. 4615-4621
NEOPLASIA
Human myeloma cells stimulate the receptor activator of nuclear
factor- B ligand (RANKL) in T lymphocytes: a potential role in
multiple myeloma bone disease
Nicola Giuliani,
Simona Colla,
Roberto Sala,
Matteo Moroni,
Mirca Lazzaretti,
Silvia La Monica,
Sabrina Bonomini,
Magda Hojden,
Gabriella Sammarelli,
Sophie Barillè,
Regis Bataille, and
Vittorio Rizzoli
From the Hematology Departments of Internal Medicine
and Biomedical Science, Experimental Medicine, and Pathology,
University of Parma, Parma, Italy; and INSERM U463,
Insitut de Biologie, Nantes, France.
The biologic mechanisms involved in the pathogenesis of multiple
myeloma (MM) bone disease are not completely understood. Recent
evidence suggests that T cells may regulate bone resorption through the cross-talk between the critical osteoclastogenetic factor,
receptor activator of nuclear factor- B ligand (RANKL), and interferon  (IFN-) that strongly suppresses
osteoclastogenesis. Using a coculture transwell system we found that
human myeloma cell lines (HMCLs) increased the expression and
secretion of RANKL in activated T lymphocytes and similarly purified MM
cells stimulated RANKL production in autologous T lymphocytes. In
addition, either anti-interleukin 6 (anti-IL-6) or anti-IL-7
antibody inhibited HMCL-induced RANKL overexpression. Consistently, we
demonstrated that HMCLs and fresh MM cells express IL-7 mRNA and
secrete IL-7 in the presence of IL-6 and that bone marrow (BM) IL-7
levels were significantly higher in patients with MM. Moreover, we
found that the release of IFN- by T lymphocytes was reduced in
presence of both HMCLs and purified MM cells. Furthermore, in a stromal cell-free system, osteoclastogenesis was stimulated by conditioned medium of T cells cocultured with HMCLs and inhibited by recombinant human osteoprotegerin (OPG; 100 ng/mL to 1 µg/mL). Finally,
RANKL mRNA was up-regulated in BM T lymphocytes of MM patients with severe osteolytic lesions, suggesting that T cells could be involved at
least in part in MM-induced osteolysis through the RANKL overexpression.
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