Abstract 3282: Host-derived MMP-13 mediates multiple myeloma-induced osteolysis
Authors: Lo Chen Hao , Shay Gemma , Lynch Conor C. 
Published: July 2016

Myeloma cells promote osteolysis and suppress osteogenesis in the bone microenvironment by regulating osteoclasts (OCL) and osteoblasts (OBL), respectively. Patients often suffer painful, osteoporotic bone status as diseases progresses. Bone consists of 90% type-I collagen, which is degraded by OCL derived cathepsin K during regular bone remodeling. While bisphosphonates delay pathological fracture, they have little impact on overall survival; therefore, development of new therapies is crucial. Matrix metalloproteinase-13 (MMP-13) is an enzyme involved in type-I collagen degradation and resorption. Immunohistochemical staining of a panel of human myeloma biopsies (n = 15) show high MMP-13 expression predominantly in bone stroma and to a lesser extent in the myeloma compartment. Consistent with previous reports, MMP-13 expression localizes to mesenchymal stromal cells (MSC) and OBLs rather than OCLs. Further supporting these observations, analysis of publically available data sets revealed upregulation of MMP-13 expression in MSCs co-cultured with myeloma cells (1.81 LogFC, p&lt;0.05). Based on this rationale, we examined whether stromal MMP-13 plays a role in myeloma progression.

To test our hypothesis, we generated immune-compromised MMP-13-null mice on a C57BL/6 background for ex vivo and in vivo studies. Mouse myeloma cell line, 5TGM1, homes to the skeleton and progresses upon tail vein injection in this model. Our in vivo studies showed that 5TGM1-bearing MMP-13-null mice had significantly improved overall survival compared to wild-type controls (Mean 39 vs. 43 days; p&lt;0.05). Interestingly, we detected no difference in tumor burden between wild-type and MMP-13-null groups, by bioluminescence or IgG2b quantification. We observed significantly less bone degradation in the MMP-13 null mice compared to controls as determined by μCT and histomorphometry. Surprisingly, however, tartrate-resistant acid phosphatase (TRAP) staining in bone sections showed no difference in OCL numbers and size in vivo, but ex vivo OCL differentiation cultures demonstrated fewer (Mean 89 vs. 16; p&lt;0.05) and smaller (Mean 29 vs. 20 μm; p&lt;0.05) OCLs in the MMP-13-null group. Furthermore, we note that OCLs derived from MMP-13-null bone marrow have a reduced capacity to resorb bone mimetic (24% reduction; p&lt;0.05). Time course analyses indicate OCL formation is delayed in MMP-13-null cultures, and may partially explain observed differences between groups in vivo. Mechanistically, we are assessing MMP specific cross-linked carboxy-terminal telopeptide of type-I collage (ICTP) fragments in sera of tumor-bearing MMP-13-null and wild-type animals. Taken together, the data suggests that host stroma-derived MMP-13 contributes to myeloma progression and bone turnover, by regulating the formation and functionality of OCLs. The outcomes of our study provide rationale for the use of MMP-13 specific inhibitors in the treatment of multiple myeloma.

Citation Format: Chen Hao Lo, Gemma Shay, Conor C. Lynch. Host-derived MMP-13 mediates multiple myeloma-induced osteolysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3282.