Notch receptors regulate multiple myeloma-driven osteoclastogenesis

Multiple myeloma (MM) is unique among hematological malignancies for its association to skeletal destruction causing hypercalcemia, bone pain and increased risk of fractures. MM cells are able to induce a disregulation in the equilibrium between bone formation and bone resorption by recruiting osteoclast (OC) precursors and facilitating osteoclastogenesis. The role of Notch signalling in skeletal development and tissue remodelling and its hyperactivation in MM prompted us to evaluate if Notch participates in MM-induced osteoclastogenesis. Our results indicate that Notch inhibition impairs MM-mediated OCs differentiation, reducing the frequency and size of TRAP+ multinucleated cells. Accordingly Notch pathway controls TRAP gene expression in OCs. Finally, Notch plays a role in the regulation of key pathways active in osteoclastogenesis like RANK/RANKL and CXCR4/CXCL12. This data support a the rationale for a Notch-targeted therapy for the treatment of MM associated bone disease.