Galectin 3 and MMP-9 relation with spontaneous osteoclastogenesis in bone marrow from advanced breast cancer patients.

FERNÁNDEZ VALLONE VB; CHOI HOSOON; BORDENAVE RH; BATAGELJ E; FELDMAN L; DIMASE F; CHASSEING NA

Lyons

Conferencia; 12th Internacional Conference on Cancer –Induced Bone Dissease. IBMS.; 2012

IBMS

Background: The bone osteolytic metastasis is one of the worst complications for advanced breast cancer patients (BCP). Bone imbalance towards osteoclastogenesis seems to be crucial for bone metastasis development. Most of the mechanisms that regulate bone formation and bone resorption are related with mesenchymal stem cells (MSC) from bone marrow (BM). We have previously observed that MSC from untreated advanced BCP (ductal infiltrative carcinoma, stage IIIb, without bone and/or BM metastasis and without any bone metabolic disease) have lower cloning efficiency for colony forming units-fibroblast (CFU-F) and lower osteogenesis capacity than MSC from healthy volunteers (HV). We have also shown that BCP develop spontaneous osteoclastogenesis from BM hematopoietic precursors in vitro. So, bone imbalance occurs even before bone metastasis appearance. Galectin 3 (Gal3) released by hematopoietic cells, mostly under inflammatory conditions, inhibits osteoclastogenesis. Its cleavage by metalloproteinases such as MMP-9, produced by stromal cells, not only lets osteoclastogenesis process to proceed but also favors angiogenesis and tumor progression. Methodology: mononuclear cells from BM of BCP (n=8) and HV (n=8) were cultured to obtain CFU-F. Medium was changed at day 7 and the culture was stopped at day 14. Condition medium (CM) from day 7 and 14 were harvested and stored until use. ELISA for Gal3 was assayed in CM from 7 day (d). Zymography for MMP-9 activity was made over CM from 14d. Results: 7d CM from BCP have lower levels of Gal3 than those from HV. Values are expressed as ng/ml (X+/-SE): 28.70+/-4.06 and 15.56+/-1.98 for BCP and HV respectively (Unpaired t-Test with Welch´s correction; p=0.05). MMP-9 gelatinolytic activity is higher in CM from CFU-F 14d from BCP than HV´s. Values of semi-quantification are expressed as relative units: 1.72+/-0.33 and 0.82+/-0.07 for BCP and HV respectively (Unpaired t-Test with Welch´s correction; p=0.05). Conclusions: Lower levels of Gal3 may not be able to inhibit osteoclastogenesis. Higher levels of MMP-9 promote osteoclatogenesis directly and also by Gal3 cleavage. Finally, Gal3 and MMP-9 are involved in bone imbalance towards bone resorption in addition to other factors such as RANKL, OPG, Dkk-1, MIF, GM-CSF and ICAM-1 as we previously reported. BoneKey abstract P82, Vol 9 (S48), 2012 (www.nature.com/bonekey) ISSN: 1940-8692 (poster presentation).