Human myeloma cells stimulate the receptor activator of nuclear factor-κB ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease

Abstract

The biologic mechanisms involved in the pathogenesis of multiple myeloma (MM) bone disease are not completely understood. Recent evidence suggests that T cells may regulate bone resorption through the cross-talk between the critical osteoclastogenetic factor, receptor activator of nuclear factor-B ligand (RANKL), and interferon ␥ (IFN-␥) that strongly suppresses osteoclastogenesis. Using a coculture transwell system we found that human myeloma cell lines (HMCLs) increased the expression and secretion of RANKL in activated T lymphocytes and similarly purified MM cells stimulated RANKL production in autologous T lymphocytes. In addition, either anti-interleukin 6 (anti-IL-6) or anti-IL-7 antibody inhibited HMCL-induced RANKL overexpression. Consistently, we demonstrated that HMCLs and fresh MM cells express IL-7 mRNA and secrete IL-7 in the presence of IL-6 and that bone marrow (BM) IL-7 levels were significantly higher in patients with MM. Moreover, we found that the release of IFN-␥ by T lymphocytes was reduced in presence of both HMCLs and purified MM cells. Furthermore, in a stromal cell-free system, osteoclastogenesis was stimulated by conditioned medium of T cells cocultured with HMCLs and inhibited by recombinant human osteoprotegerin (OPG; 100 ng/mL to 1 g/mL).

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction

“…[41][42][43] Interestingly, our data suggest that other than angiogenic cytokines, HIF-1a suppression affects expression and production of MM-derived pro-osteoclastogenic factors that are known to be involved in osteoclast formation and bone destruction such as CCL3/MIP1a 44 and IL-7. 45 To the best of our knowledge, this is the first time that the capacity of HIF-1a has been reported to regulate pro-osteoclastogenic cytokine in MM cells, although the evidence that CCL3/MIP1a and IL-7 are potential target genes of HIF-1a has been shown in other cell types such as acute myeloid leukemia cells for CCL3/MIP1a 46 and mesenchymal/osteoblastic cells for IL-7. 47 To evaluate the role of HIF-1a as a potential target in MM we used two different in vivo models: the subcutaneously and the intratibial model.…”

Deficient invariant natural killer T cells had impaired regulation on osteoclastogenesis in myeloma bone disease

“…We deduce that the level of iNKT cells frequency and production function of IFN‐γ relate to the state of bone destruction, especially osteoclastogenesis. In addition, some studies concluded that immune cells such as T cells express RANKL, but T cells also resist osteoclastogenesis by producing interferon‐γ (IFN‐γ), which counterbalance the action of RANKL 4, 7, 8. iNKT cells acting as a special T cell may be involved in bone destruction, especially osteoclastogenesis.…”

“…As we all know, osteoclastogenesis and activation of bone resorption are regulated by the RANK/RANKL/OPG axis 3. Immune cells, such as T cells, express RANKL, which contributed to the pathogenesis of MBD 4, 5, 6. While T cells also resist osteoclastogenesis by producing interferon‐γ (IFN‐γ), which counterbalance the action of RANKL 4, 7, 8.…”

“…Immune cells, such as T cells, express RANKL, which contributed to the pathogenesis of MBD 4, 5, 6. While T cells also resist osteoclastogenesis by producing interferon‐γ (IFN‐γ), which counterbalance the action of RANKL 4, 7, 8. Meanwhile, several cytokines are involved in osteoclastogenesis, such as interleukin‐17 (IL‐17), produced by Th17 cells, is shown to active OCs and induce bone resorption,9 whereas IL‐4 produced by B, Th1 and Th2 cells has an antiosteoclastogenic effect 10, 11…”

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

“…Overexpression of RANKL and decreased OPG expression in myeloma are illustrated by the high levels of sRANKL and the low level of OPG measured by ELISA in the serum of patients with myeloma compared with their respective controls (Terpos et al, 2003). One interesting point to note is that induction of these responses was dependent on cell-to-cell contact, as another transwell system showed no effect on RANKL expression (Giuliani et al, 2002).…”