IPSC-DERIVED OSTEOCLASTS: A NEW TOOL TO STUDY MULTIPLE MYELOMA INDUCED OSTEOLYSIS

Multiple myeloma (MM) is the second most common hematological
malignancy in adults characterized by clonal proliferation of plasma
cells. The use of novel therapeutic drugs has led to a substantial
improvement in the overall survival of MM patients during the last 15
years. This extension of life expectancy has revealed the impact of secondary cancer-induced pathologies. More specifically, up to 90% of MM
patients develop cancer-induced bone lesions throughout the course
of their disease due to excessive bone resorption and suppression
of bone formation, which is a major cause of morbidity and mortality.
Whereas an increase in osteoclast (OC) numbers and activity has been
identified to be responsible for the osteolysis in MM, the mechanisms
resulting from the OC and MM cell interactions are very poorly understood. This is partly due to the difficulty to isolate and culture primary
OCs, as well as the highly variable differentiation of OCs from CD14+
monocytes. Here we present induced pluripotent stem cells (iPSCs) as
a valuable tool to efficiently and reliably generate OCs (iOCs), allowing
to investigate the bidirectional interactions between OCs and MM cells.
These iOCs are multinucleated, stain for TRAP by immunocytochemistry, and express typical genes, like NFATC1, CTSK, MMP9, CALCR, CA2,
and TCIRG1, resembling primary OCs. Moreover, testing their resorption
capacity, using bovine bone slices, they clearly show the ability to generate both pits and trenches in the bone surface. Next, we tested these
iOCs in the context of MM and show that co-culture of iOCs with MM
cells, using a wide variety of MM cell lines, results in increased MM cell
proliferation, as well as drug resistance. In turn the MM cells promote
the bone resorption mediated by iOCs when cultured on bone slices.
Finally, we investigated whether interleukin 6 (IL-6), a key cytokine in
the pathogenesis of MM, is regulated through this interaction. Indeed
coculture with MM cells results in an increase in the expression of IL6,
both mRNA and protein, in iOCs. Taken together, we demonstrate that
iPSC-derived OCs can serve as an reliable platform to study the interactions between MM cells and OCs that result in osteolysis in more detail.