Spontaneous osteoclastogenesis in bone marrow and peripheral blood of advanced breast cancer patients.

FERNÁNDEZ VALLONE VB; OTAEGUI J; DIMASE F; BATGELJ E; FELDMAN L; BORDENAVE RH; CHASSEING NA

Austin, Texas.

Simposio; 5th Internacional Conference on Mesenchymal and Non Hematopoietic Stem Cells.; 2009

International Society for Cellular Therapy.

Most of advanced breast cancer patients (BCP) develop osteolytic bone metastasis that is a result of an imbalance between osteogenesis and osteoclastogenesis. Previously we found in BCP a decrease of the cloning efficiency of bone marrow (BM)-MSCs and in the osteogenic differentiation compared to healthy volunteers(HV). Osteoblast and MSCs regulate osteoclastogenesis so we studied the osteoclastogenic differentiation of BM-mononuclear cells (MNC) and peripheral blood (PB)-monocytes (Mo) from untreated advanced BCP without bone disease. Moreover we studied the effect of the conditioned medium (CM) of MNC cultures from BM-BCP over the osteoclastogenic differentiation of HV-PB-Mo and evaluated some osteoclastogenic factors. Results: we observed spontaneous osteoclastogenesis (SpOC) in BM-patients (osteoclasts(OC)%= 36.9+/-1.9) non-responsive to VitD3, meanwhile no SpOC was observed in HV (but did respond to Vit D3 OC%=9.8+/-0.6). We also found SpOC in PB, BCP and HV (OC%=25.7+/-0.5 vs 5.9+/-3.5;p=0.002). % of increase by sRANKL: =8.7+/-0.9 and =26.6+/-3.7 (p=0.003). BCP-CM treatment induced osteoclastic differentiation of HV-PB-Mo in similar way to sRANKL (34.6+/-1.9 vs 32.6+/-2.5). OC from patients were of a higher size and number of nucleus/cell. SpOC in BM could be related to the major mRANKL expression observed in MSCs from BM-BCP vs HV(+++vs++), due to the lower OPG levels that MSCs from BM-BCP release during the first 7 days of CFU-F than HV (74.4+/-8.8 vs 172.6+/-48.3 pg/ml, p=0.036). BCP presented significant higher levels of osteoclastogenic factors as GM-CSF (98+/- 4 vs 7.8pg/ml; in 7 days CFU-F CM) and sICAM (230+/-11 vs 170+/-9, in BM-plasma) compared to HV; and lower levels of IL-10 (14+/-2 vs 33+/- 4pg/ml; in BM-plasma) which is anti-osteoclastogenic factor. We cannot discard other soluble factors present in BM-CM that could stimulate the differentiation of GM-progenitors and PB-Mo. Finally PB-SpOC could be related to higher levels of sRANKL and Dkk-1 observed in BCP-PB plasma compared to HV (203 +/-37 vs 78pg/ml and 11,361+/-1,299 vs 7,268+/-1,221;p=0.03). Conclusion: we consider important the study of the osteoclastogenic potential of BM-progenitors and PB-Mo as possible prognostic factor of future bone disorders that may favor the invasion of BCcells into bone.