Soluble receptor activator of nuclear factor κB ligand–osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index

Abstract Interaction between receptor activator of nuclear factor κB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRP), and β2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We generated a prognostic index based on these factors that divided our patients into 3 risk groups. The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively. Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.

Download Full-text

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

Blood ◽

10.1182/blood-2002-04-1121 ◽

2002 ◽

Vol 100 (13) ◽

pp. 4615-4621 ◽

Cited By ~ 179

Author(s):

Nicola Giuliani ◽

Simona Colla ◽

Roberto Sala ◽

Matteo Moroni ◽

Mirca Lazzaretti ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Lymphocytes ◽

Bone Disease ◽

Nuclear Factor Κb ◽

Myeloma Cell ◽

Nuclear Factor ◽

Free System ◽

Receptor Activator ◽

Ifn Γ

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-κB ligand (RANKL), and interferon γ (IFN-γ) 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-γ 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 μg/mL). Finally, RANKL mRNA was up-regulated in BM T lymphocytes of MM patients with severe osteolytic lesions, suggesting that T cells could be involved at least in part in MM-induced osteolysis through the RANKL overexpression.

Download Full-text

Circulating Osteoprotegerin and Receptor Activator for Nuclear Factor κB Ligand: Clinical Utility in Metabolic Bone Disease Assessment

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-0794 ◽

2005 ◽

Vol 90 (11) ◽

pp. 6323-6331 ◽

Cited By ~ 140

Author(s):

Angela Rogers ◽

Richard Eastell

Keyword(s):

Bone Disease ◽

Clinical Utility ◽

Metabolic Bone Disease ◽

Nuclear Factor Κb ◽

Disease Assessment ◽

Nuclear Factor ◽

Metabolic Bone ◽

Receptor Activator

Download Full-text

The role of serum osteoprotegerin and receptor–activator of nuclear factor-κB ligand in metabolic bone disease of women after obesity surgery

Journal of Bone and Mineral Metabolism ◽

10.1007/s00774-015-0712-0 ◽

2015 ◽

Vol 34 (6) ◽

pp. 655-661 ◽

Cited By ~ 6

Author(s):

José A. Balsa ◽

Christian Lafuente ◽

Jesús M. Gómez-Martín ◽

Julio Galindo ◽

Roberto Peromingo ◽

...

Keyword(s):

Obesity Surgery ◽

Bone Disease ◽

Metabolic Bone Disease ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Metabolic Bone ◽

Receptor Activator

Download Full-text

The OPG/TRAIL Interaction in an In Vitro Osteoclastogenesis Model Derived from Human Multiple Myeloma-Bone Disease.

Blood ◽

10.1182/blood.v104.11.2361.2361 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2361-2361

Author(s):

Stefano Molica

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Bone Disease ◽

Nuclear Factor Kappa B ◽

Nuclear Factor ◽

Nuclear Factor Kappa ◽

Trail Receptors ◽

Receptor Activator

Abstract The development of multiple myeloma (MM)-bone disease is mediated by increased recruitment and activity of osteoclasts (OCs). Osteoclastogenesis is regulated by a complex signaling system, that involves receptor activator of nuclear factor-kappa B (RANK), receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG), all belonging to the Tumor Necrosis Factor (TNF) family. The aims of our study were to investigate: the MM T cell involvement in osteoclastogenesis, and the expression of the major osteoclastogenic mediators. Unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs) isolated from 32 MM patients with or without osteolytic bone lesions, and parallel T cell-depleted cultures were used as in vitro osteoclastogenesis models. In addition, unstimulated and unfractionated PBMC cultures from 32 controls with nonneoplastic disease without any skeletal involvement were also established. Our results showed that the OCs derived from MM-bone disease PBMCs spontaneously developed and displayed a longer survival in a T cell-dependent way. Differently in T cell-depleted MM PBMC cultures, the addition of macrophage-colony stimulating factor (M-CSF) and RANKL was necessary to promote the formation of OCs, that however did not exibit a longer survival. MM-bone disease T cells overexpressed RANKL, OPG and TNF-related apoptosis inducing ligand (TRAIL), also detected in large amounts in the culture media. Despite high OPG levels, the persistence of osteoclastogenesis in our system can be related to the interaction between OPG and TRAIL, that were coimmunoprecipitated by a monoclonal antibody (mAb) against TRAIL. The evidence that TRAIL binds to OPG blocking OPG anti-osteoclastogenic effect is also supported by the addition of different concentrations of functional anti-TRAIL mAb, significantly decreasing the OC formation. The OCs developed from MM-bone disease PBMCs expressed a T cell-modulated balance of death and decoy TRAIL receptors. In particular, we found these OCs overexpressed TRAIL decoy receptor DcR2 in the presence of T cells, and death receptor DR4 in the T cell-depleted cultures. In conclusion, our results highlight that MM-bone disease T cells support the spontaneous OC formation with longer survival, involving the OPG/TRAIL interaction and the unbalanced OC expression of TRAIL death and decoy receptors.

Download Full-text