Matrix Metalloproteinses-13 (Collagenase-3) Secreted by Multiple Myeloma Cells Enhances the Bone Resorptive Activity of Osteoclasts.

Osteolytic bone disease is a frequent complication of multiple myeloma (MM) that is characterized by reduced bone formation and increased bone resorption. MM cells produce several cytokines causing dysregulation of the bone remodeling process that results in excessive bone resorption mediated by activated osteoclasts (OCLs). Matrix metalloproteinases (MMPs) play a critical role in tumor invasion and progression in many solid tumors such as breast cancer but the role of MMPs in MM has have not been well elucidated.

We analyzed the MMP expression profiles (MMP1, 2, 3, 7, 8, 12, 13) of MM cells and found very high expression (400-fold higher) of MMP13 compared to other MMPs. Tissue array analysis for MMP-13 expression in MM tumor samples and normal control tissue indicated that MMP13 was only highly expressed in MM tumor samples. ELISA analysis of serum samples revealed a positive correlation of MMP13 expression with MM bone disease. MMP13 was not detectable in the sera of healthy donors, whereas 62% of MM patients expressed MMP13 in their serum samples, among which 87% had extensive bone disease. Co-culture of MM cells with primary bone marrow stromal cells (BMSC) resulted in a significant (P<0.001) increase (up to 14-fold) of MMP13 secretion by MM cells. RT-PCR analysis indicated that the expression of MMP13 gene in MM cells was markedly enhanced by BMSC conditioned medium, suggesting that BMSC-secreted soluble factors, instead of direct cellular interactions, induce MMP13. Functional inactivation of different cytokines with neutralizing antibodies identified IL-6 as a critical cytokine for the induction of MMP13. Electromobility shift assays showed that IL-6 mediated AP-1 activation promotes MMP13 transcription. Importantly, MMP13 significantly enhanced osteoclastic bone resorption on dentin slices induced by RANKL plus M-CSF. However, the strong induction of bone resorption was not derived from increased OCL formation since MMP13 only slightly increased OCL numbers. MMP13 significantly increased the OCL size as well as the nuclear number/OCL which increases the bone resorption activity per osteoclast.

Our results suggest that MMP13 augments the pathogenic process of osteolytic lesions in MM by increasing the bone resorption capacity/OCL. These results suggest that targeting MMP13 may represent a novel approach to ameliorate osteolytic lesions in MM.

Roodman:Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Celgene: Consultancy; Acceleron: Consultancy. Lentzsch:Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy.