LIGHT INVOLVEMENT IN MULTIPLE MYELOMA-OSTEOLYTIC BONE DISEASE

Background: Multiple myeloma (MM)-osteolytic bone disease occurs in about 70% of newly diagnosed patients, and up to 90% at relapse. It is characterized by an unbalanced bone remodelling, due to increased osteoclast (OC) activity and impaired osteoblast repair. Osteoclastogenesis is regulated by members of TNF superfamily. Among these, there is LIGHT/TNFSF14 recently implicated in the pathogenesis of joint diseases with increased bone resorption, as the rheumatoid arthritis. LIGHT is expressed by activated T-cells, monocytes, granulocytes, spleen cells, and immature dendritic cells, and it is described as a potent T-cell co-stimulatory molecule. Aims: Here, we purposed to investigate a possible role of LIGHT in the mechanisms of the enhanced osteoclastogenesis occurring in MM-osteolytic bone disease. Methods: Peripheral blood (PB) and bone marrow (BM) aspirates were obtained from 40 patients (23M/17F, median age: 64 years), newly diagnosed as having symptomatic MM with or without osteolytic bone disease, smoldering MM (sMM) or Monoclonal Gammopathy of Undetermined Significance (M.G.U.S.). Osteolytic lesions were detected by skeleton standard radiography, and in some cases also by spine and pelvis nuclear magnetic resonance. The control group included PB and BM aspirates from 15 patients with nonneoplastic disease without any skeletal involvement as well as PB from 25 healthy donors matching for age and sex with the patients’ group. Patients and controls gave their written informed consent to the study, approved by the local Ethical Committee and performed according to the Declaration of Helsinki. By means of flow cytometry, Western Blotting and real-time PCR, LIGHT expression was evaluated in freshly purified CD14+ monocytes, CD2+ T-cells and neutrophils from PB and BM aspirates of patients and controls. OCs were obtained from unfractionated PB mononuclear cells (PBMCs) cultured in the presence or in the absence of an anti-LIGHT neutralizing monoclonal antibody (mAb). Mature OCs were identified as multinucleated tartrate-resistant acid phosphatase (TRAP) positive cells. Results: In the CD14+ monocytes, CD2+ T-cells and neutrophils isolated from PB and BM of patients with MM-osteolytic bone disease, at both protein and mRNA levels LIGHT was found more expressed than in the cells isolated from the patients with symptomatic MM without bone disease, sMM, M.G.U.S, nonneoplastic disease without any skeletal involvement, and healthy donors. The in vitro effect of the anti-LIGHT mAb on osteoclastogenesis resulted in a significant reduction of the OC formation (p<0.001). Summary and Conclusions: Our findings support a possible involvement of LIGHT in the mechanisms of the osteoclastogenesis occurring in MM-osteolytic bone disease.