A hallmark of Multiple Myeloma is skeletal colonization resulting in painful osteolytic lesions. Matrix metalloproteinase-13 (MMP-13) is a type-1 collagenase largely expressed by mesenchymal stromal cell (MSCs) in the bone tissue. In agreement, immunohistochemical staining of human myeloma biopsies demonstrated the localization of MMP-13 to the stromal compartment with expression in a subset of myeloma cells. This observation was further supported by studies showing that co-culture of myeloma cells with human MSCs, strongly up regulated MMP-13 expression in MSCs (1.81 LogFC, P<0.05.) Given the role of MMP-13 in bone matrix turnover and the osteolytic nature of the disease, we hypothesized that host-derived MMP-13 plays a potentially key role in myeloma progression and colonization of the skeleton.
Inoculation of 5TGM1-Luc into immunodeficient wild-type or MMP-13−/− mice revealed that MMP-13 significantly contributed to overall survival (mean 39 vs 43 days; P<0.05). Unexpectedly, we observed no difference in tumor burden between the groups. However, MMP-13/− mice had significantly more bone volume compared to controls as determined by histomorphometry, X-ray and μCT (0.5 vs 0.23 ratio; P<0.05). In vitro, we noted that fewer and smaller osteoclasts formed in the MMP-13−/− bone marrow cultures compared to control (Mean number 89 vs 16; P<0.05). This was associated with a reduced bone resorptive ability when osteoclasts were culture on a bone mimetic (24% reduction; P<0.05). In keeping with immunohistochemical studies and the literature, immunofluorescent staining of wt bone marrow revealed MMP-13 expression to be absent from osteoclasts and largely confined to MSCs. These data imply that MMP-13, derived from bone mesenchymal stromal cells contributes to myeloma progression by enhancing osteoclastogenesis and bone degradation. The tissue restrictive expression of MMP-13 makes it an attractive therapeutic target for the treatment of multiple myeloma.
14 - 17 May 2016
European Calcified Tissue Society