Multiple myeloma (MM) is characterized by increased osteoclast (OCL) activity that results in bone destruction and purely lytic lesions in ~80% patients. The excessive bone resorption is mediated by OCLs, which are activated by factors secreted by MM cells and their microenvironment. This is supported by the finding that MM cells are always located in close association with sites of active bone resorption. Matrix metalloproteinase 13 (MMP13) belongs to a family of endopeptidases capable of degrading and remodeling all extracellular matrix (ECM) components. We recently found that secretion of MMP13 by MM cells is up to 400-fold higher than other MMPs. Primary tissue array analysis showed that MMP13 is highly expressed in MM cells, but not in normal plasma cells. ELISA of MM patient sera revealed a 100% correlation between detection of MMP13 protein and bone disease while MMP13 was undetectable in healthy donors. In vitro MMP13 increased bone resorption, where its enhancing effects were associated with dramatically increased OCL size and nuclear number/OCL, suggesting that MMP13 induces fusion of OCL precursors. Further, OCL generated from Mmp13-/- mice showed a significantly decreased number of nuclei and average OCL cell size and bone resorption capacity compared to WT mice. Addition of MMP13 reversed the fusion defect of Mmp13-/- MNCs. Further, MMP13 was strongly upregulated in MM cells in response to IL-6 and EMSA revealed that IL-6-mediated AP-1 activation promoted MMP13 transcription. Dendritic cell-specific transmembrane protein (DC-STAMP), essential for cell-cell fusion of preosteoclasts, was upregulated by exogenous MMP13. Taken together, we hypothesize that myeloma cell-derived MMP13 plays a pivotal role in MM-induced bone destruction. We contend that the upregulation of IL-6 by the MM microenvironment triggers the secretion of MMP13 in MM cells. In turn, MMP13 induces DC-STAMP, resulting in increased OCL activity, bone resorption and ECM degradation. As such, targeting MMP13 may represent an effective and new approach to treat myeloma bone disease (MMBD). To test these hypotheses, we will 1) investigate the autocrine and paracrine mechanisms of MMP13 induction in MM cells, 2) investigate the mechanisms of enhancing of OCL formation and activity by MMP13 and 3) confirm in vivo the role of MMP13 in the development of myeloma-induced osteolytic bone lesions. A successful completion of this work will be crucial for the achievement of our overall goal to identify novel therapies for myeloma bone disease.
Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by the development of devastating lytic bone disease. We found that Matrix Metallopeptidase13 (MMP13) is secreted at high levels by multiple myeloma cells and strongly induces osteoclast formation/activity resulting in increased bone resorption. This high relevance of our finding is supported by the fact that MMP13-/- mice exhibit increased bone mass. In the current proposal we hypothesize that MMP13 plays a critical role in induction of osteoclast fusion resulting in the development of MM lytic bone disease. The confirmation of our hypothesis will provide novel insights into the development of lytic bone lesions in MM and provide novel treatment approaches for MM bone disease.
|Li, Shirong; Fu, Jing; Wang, Hui et al. (2018) IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation. Blood Adv 2:492-504|
|Liu, Ailing; Li, Shirong; Donnenberg, Vera et al. (2018) Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation. Haematologica 103:1688-1697|
|Fu, Jing; Li, Shirong; Feng, Rentian et al. (2016) Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease. J Clin Invest 126:1759-72|
|Li, Shirong; Fu, Jing; Lu, Caisheng et al. (2016) Elevated Translation Initiation Factor eIF4E Is an Attractive Therapeutic Target in Multiple Myeloma. Mol Cancer Ther 15:711-9|