MYELOMA CELLS UP-REGULATE INTERLEUKIN-6 SECRETION IN OSTEOBLASTIC CELLS THROUGH CELL-TO-CELL CONTACT BUT DOWN-REGULATE OSTEOCALCIN

Previous studies have shown that bone marrow, especially the bone micr oenvironment, may play an important role in the pathogenesis of multip le myeloma (MM). To elucidate the relationship between myeloma cells a nd bone cells, mainly osteoblasts, we have established a coculture sys tem between two interleukin-6 (IL-6)-dependent myeloma cell lines, XG1 and XG6, and the osteosarcoma cell lines Saos2 and MG63. Both osteosa rcoma cell lines have retained major functions of normal osteoblasts; principally, the capacity to produce hematopoietic growth factors (inc luding IL-6) and osteocalcin, a noncollagenic protein essential in the bone formation process. Because IL-6 is a critical growth factor in M M, we have examined the IL-6 osteoblastic cell production in our cocul ture system. XG1 cells strongly upregulate IL-6 production by MG63 and Saos-2 cells. Of major interest, the triggering of IL-6 is totally de pendent on the physical contact between myeloma cells and osteoblastic cells, contact that is partly mediated by CD44, CD56, and fibronectin interactions. Osteocalcin production by MG63 and Saos-2 cells has pre viously been shown to be dependent on 1,25-(OH)(2)D-3. We demonstrate that XG1 and XG6 cells reduced the amount of osteocalcin in MG63 cocul ture cell supernatants, a reduction that is partly mediated by a solub le factor and by cell-to-cell contact. Notably, whereas one of the mye loma cell lines, XG6, has lost its capacity to stimulate IL-6 producti on by osteoblastic cell lines, both XG1 and XG6 cell lines remain able to reduce the osteocalcin amount, indicating that IL-6 and osteocalci n levels are regulated by two different pathways. In conclusion, these data strongly support the concept that the bone microenvironment is d irectly modified by contact with myeloma cells and are consistent with the characteristics observed in vivo in patients with MM patients, ie , abnormally high IL-6 and low osteocalcin levels, respectively. (C) 1 995 by The American Society of Hematology.