NEW YORK (Reuters Health) - Overexpression of a gene - dickkopf1 (DKK1) - by myeloma cells fuels the generation and maintenance of focal osteolytic lesions in multiple myeloma, results of a study suggest. The hope is that this will lead to the development of specific drug therapy for this condition.
“We now have definitive evidence of a molecular mechanism for myeloma-associated bone destruction,” Dr. John D. Shaughnessy, Jr. from the University of Arkansas for Medical Sciences told Reuters Health. “Knowing the molecule that causes the pathology means we can develop drugs that specifically antagonize DKK1 function,” he added.
Using oligonucleotide microarray technology, Dr. Shaughnessy and colleagues examined the expression of roughly 10,000 genes by purified plasma cells from the bone marrow of multiple myeloma patients with (n=137) and without (n=36) bone lesions and 45 normal controls.
Four genes, including DKK1, were significantly overexpressed by plasma cells from myeloma patients with focal lesions, the investigators report in the December 25th issue of The New England Journal of Medicine. They zeroed in on the DKK1 gene because it codes for a secreted protein that has previously been linked to the function of osteoblasts.
In bone marrow-biopsy specimens, only myeloma cells contained detectable DKK1 protein. Moreover, elevated DKK1 levels in bone marrow plasma and peripheral blood correlated with focal osteolytic lesions.
The researchers suspect that the DKK1 produced by myeloma cells tips the balance between osteoblasts and osteoclasts in favor of bone resorption. “DKK1 paralyzes the bone forming osteoblasts and when compounded with the hyperactivation of bone resorbing osteoclasts, leads to a net loss of bone,” Dr. Shaughnessy explained.
The researchers are currently in the early phases of developing and testing several compounds aimed at disabling DKK1.
“We envision that combined use of bisphosphonates, which prevent osteoclast activation, with a drug that neutralizes DKK1 and hence reactivates osteoblasts could reverse or prevent bone loss in myeloma,” Dr. Shaughnessy said.
Furthermore, because DKK1 inhibits Wnt signaling, which is central to normal osteoblast biology, “there is strong reason to believe that perturbations of this pathway may be at the root of other cancer-related bone disorders as well as postmenopausal osteoporosis,” Dr. Shaughnessy added.
Source: N Engl J Med 2003;349:2483-2494. [ Google search on this article ]
MeSH Headings:Biological Sciences: Biology: Gene Expression Regulation: Genetics: Genetics, Biochemical: Molecular Biology: Gene Expression Regulation, Neoplastic: Biological SciencesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
