The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma
Erming Tian, B.S., Fenghuang Zhan, Ph.D., Ronald Walker, M.D., Erik Rasmussen, M.S., Yupo Ma, M.D., Ph.D., Bart Barlogie, M.D., Ph.D., and John D. Shaughnessy, Jr., Ph.D.
The New England Journal of Medicine 349:2483-2494, December 2003

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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, dickkopf1 (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.

• Background
• Methods
  • Patients
  • Bone Imaging
  • Plasma-cell Isolation and Gene-expression Profiling
  • Immunohistochemistry
  • Enzyme-Linked Immunosorbent Assay
  • Osteoblast-Differentiation Assays
  • Statistical Analysis
• Results
  • Gene-expression Profiling of Myeloma Cells
  • Synthesis of DKK1 by Plasma Cells
  • DKK1 in Bone Marrow Plasma
  • Effect of Bone Marrow Plasma on Osteoblast Differentiation in Vitro
• Discussion
• References

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