| First Author | Lo CH | Year | 2021 |
| Journal | Cancer Res | Volume | 81 |
| Issue | 9 | Pages | 2415-2428 |
| PubMed ID | 33526510 | Mgi Jnum | J:305551 |
| Mgi Id | MGI:6706772 | Doi | 10.1158/0008-5472.CAN-20-2705 |
| Citation | Lo CH, et al. (2021) Host-derived Matrix Metalloproteinase-13 Activity Promotes Multiple Myeloma-induced Osteolysis and Reduces Overall Survival. Cancer Res |
| abstractText | Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type-I-collagen rich bone matrix by activated osteoclasts (OCL) results in the release of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP-13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP-13 largely localizes to the stromal compartment compared to CD138+ myeloma cells. In this study, we further identified that multiple myeloma induces MMP-13 expression in bone stromal cells. Because of its ability to degrade type-I-collagen, we examined whether bone stromal derived MMP-13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild type or MMP-13 null-mice. In independent in vivo studies, MMP-13 null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared to wild type controls. Unexpectedly, no differences in type-I-collagen processing between the groups were observed. Ex vivo stromal co-culture assays showed reduced formation and activity in MMP-13-null osteoclasts. Analysis of soluble factors from wild type and MMP-13-null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP-13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP-13 catalytic activity in multiple myeloma progression, we demonstrate the in vivo efficacy of a novel and highly-selective MMP-13 inhibitor that provides a translational opportunity for the treatment of this incurable disease. |
