Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation

The pathogenesis of the bone disease of multiple myeloma

“…Myeloma cells were found to inhibit Runx2 activity and reduce osteoblast differentiation in osteoprogenitor cells; an effect that was mediated by both cell-cell contact and interleukin 7 (65). In support of a role for Runx2 in the pathophysiology of myeloma bone disease, a significant reduction in the proportion of Runx2 positive osteoblasts was observed in patients with myeloma with evidence of osteolytic bone lesions, compared to those patients with no evidence of bone disease (65).…”

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

“…Myeloma cells could suppress osteoblast differentiation by decreasing the activity of Runx2/Cbfal, the principal master transcription factor for osteoblast differentiation and bone formation (Giuliani et al, 2005).…”

“…This transcription factor is required for osteoblast and bone formation, as Runx2-/-mice demonstrate total deficiency in these two areas (Komori et al, 1997). The co culture of MM cells with osteoprogenitor cells has been shown to reduce numbers of osteoblast precursors, osteoblast differentiation markers like alkaline phosphatase, and the osteoblasts themselves, performed via blocking Run2x/Cbfal activity (Giuliani et al, 2005). This appears to be mediated primarily through cell-to-cell contact with MM and osteoprogenitor cells, involving interactions between VLA-4 on the MM cells and VCAM-1 on the osteoblast progenitors (Giuliani et al, 2005).…”

“…The co culture of MM cells with osteoprogenitor cells has been shown to reduce numbers of osteoblast precursors, osteoblast differentiation markers like alkaline phosphatase, and the osteoblasts themselves, performed via blocking Run2x/Cbfal activity (Giuliani et al, 2005). This appears to be mediated primarily through cell-to-cell contact with MM and osteoprogenitor cells, involving interactions between VLA-4 on the MM cells and VCAM-1 on the osteoblast progenitors (Giuliani et al, 2005). This is not the only cell contact interaction appearing to inhibit osteoblastogenesis, but the best characterized.…”

“…This study also showed a direct relationship between DKK-1 expression in MM cells and bone lesions in patients, indicating a mediation of bone destruction. Yet, the mechanism by which the DKK-1 production is related to bone destruction is unclear, as neutralizing DKK-1 in MM patients aids in restoration of osteoblastogenesis in mice, but not humans, indicating there are likely other mechanisms at work in conjunction with DKK-1 Wnt inhibition (Giuliani et al, 2005). One hypothesis is that DKK-1 aids in adhesion of stromal cells to MM cells, inhibiting Runx2 and activating osteoclasts (Giuliani et al, 2004).…”