BACKGROUND: Myeloma cells may secrete factors that affect the function of 
osteoblasts, osteoclasts, or both.
METHODS: We subjected purified plasma cells from the bone marrow of patients 
with newly diagnosed multiple myeloma and control subjects to oligonucleotide 
microarray profiling and biochemical and immunohistochemical analyses to 
identify molecular determinants of osteolytic lesions.
RESULTS: We studied 45 control subjects, 36 patients with multiple myeloma in 
whom focal lesions of bone could not be detected by magnetic resonance imaging 
(MRI), and 137 patients in whom MRI detected such lesions. Different patterns of 
expression of 57 of approximately 10,000 genes from purified myeloma cells could 
be used to distinguish the two groups of patients (P<0.001). Permutation 
analysis, which adjusts the significance level to account for multiple 
comparisons in the data sets, showed that 4 of these 57 genes were significantly 
overexpressed by plasma cells from patients with focal lesions. One of these 
genes, dickkopf 1 (DKK1), and its corresponding protein (DKK1) were studied in 
detail because DKK1 is a secreted factor that has been linked to the function of 
osteoblasts. Immunohistochemical analysis of bone marrow-biopsy specimens showed 
that only myeloma cells contained detectable DKK1. Elevated DKK1 levels in bone 
marrow plasma and peripheral blood from patients with multiple myeloma 
correlated with the gene-expression patterns of DKK1 and were associated with 
the presence of focal bone lesions. Recombinant human DKK1 or bone marrow serum 
containing an elevated level of DKK1 inhibited the differentiation of osteoblast 
precursor cells in vitro.
CONCLUSIONS: The production of DKK1, an inhibitor of osteoblast differentiation, 
by myeloma cells is associated with the presence of lytic bone lesions in 
patients with multiple myeloma.