Notch signaling drives multiple myeloma induced osteoclastogenesis

Abstract

Multiple myeloma (MM) is closely associated with bone destruction. Once migrated to the bone marrow, MM cells unbalance bone formation and resorption via the recruitment and maturation of osteoclast precursors.The Notch pathway plays a key role in different types of cancer and drives several biological processes relevant in MM, including cell localization within the bone marrow, proliferation, survival and pharmacological resistance.Here we present evidences that MM can efficiently drive osteoclastogenesis by contemporaneously activating Notch signaling on tumor cells and osteoclasts through the aberrant expression of Notch ligands belonging to the Jagged family. Active Notch signaling in MM cells induces the secretion of the key osteoclastogenic factor, RANKL, which can be boosted in the presence of stromal cells. In turn, MM cells-derived RANKL causes the upregulation of its receptor, RANK, and Notch2 in pre-osteoclasts. Notch2 stimulates osteoclast differentiation by promoting autocrine RANKL signaling. Finally, MM cells through Jagged ligands expression can also activate Notch signaling in pre-osteoclast by direct contact.Such synergism between tumor cells and pre-osteoclasts in MM-induced osteoclastogenesis can be disrupted by silencing tumor-derived Jagged1 and 2. These results make the Jagged ligands new promising therapeutic targets in MM to contrast bone disease and the associated co-morbidities.

Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment

“…4,[53][54][55] In MM, induction of Notch in OCL through the interaction with tumor cells has been shown to represent one of the mechanisms driving osteoclastogenesis. 2,25 In agreement with these data we found that the pharmacological inhibition of Notch with RO4929097 during OCL differentiation as well as in mature OCL results in a significant reduction in OCL number and function.…”

“…25,32 Therefore, we investigated whether the inhibition of Notch with RO4929097 could affect osteoclast (OCL) differentiation and function. Peripheral blood MNC were differentiated into OCL by treatment with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kB ligand (RANKL), with or without 1 mM RO4929097.…”

“…21 Notch signaling has been also implicated in the development of MM-associated bone disease, primarily through the stimulation of osteoclastogenesis. 25,26 Taken together, these data suggest that targeting the Notch pathway may be therapeutically beneficial for patients with MM. Here, we tested this hypothesis utilizing RO4929097, a pharmacological inhibitor of Notch/g-secretase.…”

DAPT inhibits the chondrogenesis of human umbilical cord mesenchymal stem cells

“…Finally, it plays an important role in the cell proliferation and differentiation, organ development and diseases [19]. Previous evidence has also suggested that Notch signaling participates in the chondrogenesis and the proliferation and differentiation of chondrocytes [20,21].The Notch pathway exists in the differentitation and biological processes of multiple myeloma, including cell localization with the bone marrow, proliferation, survival and pharmachological resistance [22], Jag-1 and Notch-1 exist in mammalian cells [23], some studies have indicated that Notch signaling mediated by Jag-1 plays a role in the development of many tissues [24], and has an important effect on the chondrogenesis of BMSCs [25].…”

“…Multiple myeloma cells can activate the North pathway due to the over-express of Jad-1 ligands [22,26] thus activate osteoclastogenesis. In T cell acute lymphoblastic luekaemia, Notch-1 can enhance the proliferative advantage and specific chemotactic abilities through acting in concert with chemokine receptor pathways, therefore influencing tumor cell progression and localization [27].…”