ADAM-9 (MDC-9/meltrin-γ), a member of the a disintegrin and metalloproteinase family, regulates myeloma-cell-induced interleukin-6 production in osteoblasts by direct interaction with the αvβ5 integrin

ADAM-9, a member of the a disintegrin and metalloproteinase family, contains both metalloproteinase and disintegrin domains. Myeloma cell lines express ADAM-9; however, its function and role in the pathophysiology of multiple myeloma is unknown. The aim of this study was to establish whether primary myeloma cells express ADAM-9, whether ADAM-9 regulates IL-6 production in human osteoblasts (hOBs), whether ADAM-9 interacts with specific integrin heterodimers, and the identity of downstream signaling path-ways. Primary myeloma cells demonstrated increased expression of ADAM-9 (P < .01). ADAM-9 promoted a 5-fold increase in IL-6, but not IL-1 beta mRNA, and a dose- and time-dependent increase in IL-6 production by hOBs (P < .01). IL-6 induction was inhibited by an antibody to the alpha(v)beta(5) integrin (P < .01) but not by antibodies to other integrin heterodimers. ADAM-9 was shown to bind directly to the alpha(v)beta(5) integrin on hOBs. Antibodies to ADAM-9 and a.,05 integrin inhibited myeloma cell-induced IL-6 production by hOBs (P < .01). Furthermore, inhibitors of p38 MAPK and cPLA(2), but not NF-kappa B and JAK2, signaling pathways inhibited ADAM-9-induced IL-6 production by hOBs (P < .01). These data demonstrate that ADAM-9, expressed by myeloma cells, stimulates IL-6 production in hOBs by binding the alpha(v)beta(5) integrin. This may have important consequences for the growth and survival of myeloma cells in bone.