Multiple myeloma (MM) almost exclusively expands in the bone marrow and generates devastating bone destruction. We recently reported that GM-CSF and IL-4, an inducer of dendritic cell (DC) differentiation, up-regulate TNFα converting enzyme (TACE) expression in monocytes to cleave their surface M-CSF receptor (M-CSFR), which drastically disrupts osteoclastogenesis. Because TACE activity is inhibited by TIMP3, we explored the expression of TIMP3 and its role in monocyte differentiation into osteoclasts and DCs in MM. Bone marrow stromal cells (BMSCs) secreted a large amount of TIMP3 protein whose production was further enhanced by IL-6 and TGFβ over-produced in MM bone lesions. BMSCs potently suppressed GM-CSF and IL-4-induced DC differentiation and resumed osteoclastogenesis from monocytes along with the suppression of surface M-CSFR and RANK shedding on monocytes. TIMP3 knockdown in BMSCs by TIMP3 siRNA enhanced M-CSFR shedding in monocytes in the presence of BMSCs and resumed GM-CSF and IL-4-mediated DC differentiation from monocytes, suggesting monocyte differentiation skewed by BMSC-derived TIMP3. These results suggest that TIMP3 over-produced in MM bone marrow microenvironment restores surface M-CSFR on monocytes to facilitate their downstream signaling, which causes extensive bone destruction and impaired DC differentiation in MM. TIMP3 may therefore become a novel target in the treatment of MM bone disease
