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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-09-2684.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2094-2098
PERSPECTIVE
RANK ligand and osteoprotegerin in myeloma bone
disease
Orhan Sezer,
Ulrike Heider,
Ivana Zavrski,
Christian Alexander Kühne, and
Lorenz Christian Hofbauer
From the Department of Oncology and Hematology,
Universitätsklinikum Charité, Berlin, Germany;
the Department of Trauma Surgery, University of Essen, Essen,
Germany; and the Division of Gastroenterology,
Endocrinology and Metabolism, Philipps University, Marburg,
Germany.
Myeloma bone disease is due to interactions of myeloma cells with
the bone marrow microenvironment, and is associated with pathologic
fractures, neurologic symptoms and hypercalcemia. Adjacent to myeloma
cells, the formation and activation of osteoclasts is increased, which
results in enhanced bone resorption. The recent characterization of the
essential cytokine of osteoclast cell biology, receptor activator of
NF- B ligand (RANKL) and its antagonist osteoprotegerin (OPG), have
led to a detailed molecular and cellular understanding of myeloma bone
disease. Myeloma cells induce RANKL expression in bone marrow stromal
cells, and direct RANKL expression by myeloma cells may contribute to
enhanced osteoclastogenesis in the bone microenvironment in myeloma
bone disease. Furthermore, myeloma cells inhibit production and induce
degradation of OPG. These effects result in an increased RANKL-to-OPG
ratio that favors the formation and activation of osteoclasts.
Patients with myeloma bone disease have inappropriately low serum and
bone marrow levels of OPG. Specific blockade of RANKL prevented the
skeletal complications in various animal models of myeloma, and
suppressed bone resorption in a preliminary study of patients with
myeloma bone disease.
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