Production of Lymphotoxin, a Bone-Resorbing Cytokine, by Cultured Human Myeloma Cells

I. Ross Garrett, Brian G.m. Durie, Glenn E. Nedwin, Alison Gillespie, Timothy Bringman, Massimo Sabatini, Donald R. Bertolini, Gregory R. Mundy

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295 Scopus citations


Myeloma cells destroy bone by producing an osteoclast-stimulating factor that has chemical and biological characteristics similar to the bone-resorbing activity present in the supernatants of activated leukocyte cultures. Recently, a number of bone-resorbing leukocyte cytokines have been identified, including interleukin-1, lymphotoxin, and tumor necrosis factor. We have examined the products of human myeloma cells for the presence of these bone-resorbing cytokines. In a tumor cell line derived from a patient who had myeloma with osteolytic bone lesions and hypercalcemia, we found that the myeloma cells induced bone-resorbing activity and cytotoxic activity in vitro. Most of the bone-resorbing activity and all cytotoxic activity were suppressed by neutralizing antibodies to lymphotoxin. The myeloma cells expressed both lymphotoxin and tumor necrosis factor mRNA, but no tumor necrosis factor could be detected in the cell-culture medium. Interleukin-1 mRNA was not detected in the myeloma cells, and biologic activity of interleukin-1 was not measurable in the medium harvested from the cultured cells. The bone-resorbing activity induced by recombinant tumor necrosis factor and recombinant interleukin-1 was not affected by treatment with the lymphotoxin antibodies. When lymphotoxin was infused subcutaneously into normal mice (10 μg per day for three days), their plasma calcium levels increased. We also evaluated four established cell lines derived from three other patients with myeloma, and found a similar pattern of lymphotoxin expression in each. It appears that production of the bone-resorbing cytokine lymphotoxin is related to osteoclastic bone destruction and hypercalcemia in patients with myeloma. (N Engl J Med 1987;317:526–32.), MYELOMA is characterized by extensive bone destruction, which occurs in almost all patients and is accompanied by severe and intractable pain and susceptibility to fracture. Hypercalcemia develops in many patients during the course of the disease.1 Histologic sections of bone are characterized by an increase in osteoclast activity occurring adjacent to the myeloma cells.2,3 The mechanism appears to be the production by myeloma cells of an osteoclaststimulating factor with biologic characteristics similar to those of the osteoclast-activating factor produced by normal activated leukocytes.1,4 The bone-resorbing activity present in supernatants of activated leukocyte cultures probably represents the net effect of a…

Original languageEnglish (US)
Pages (from-to)526-532
Number of pages7
JournalNew England Journal of Medicine
Issue number9
StatePublished - Aug 27 1987

ASJC Scopus subject areas

  • Medicine(all)


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