ADAM-9 (MDC-9/meltrin-gamma), a member of the a disintegrin and metalloproteinase family, regulates myeloma-cell-induced interleukin-6 production in osteoblasts by direct interaction with the alpha(v)beta5 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 pathways. Primary myeloma cells demonstrated increased expression of ADAM-9 (P < .01). ADAM-9 promoted a 5-fold increase in IL-6, but not IL-1beta 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)beta5 integrin (P < .01) but not by antibodies to other integrin heterodimers. ADAM-9 was shown to bind directly to the alpha(v)beta5 integrin on hOBs. Antibodies to ADAM-9 and alpha(v)beta5 integrin inhibited myeloma cell-induced IL-6 production by hOBs (P < .01). Furthermore, inhibitors of p38 MAPK and cPLA2, but not NF-kappaB 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)beta5 integrin. This may have important consequences for the growth and survival of myeloma cells in bone.
Karadag
Abdullah
A
Division of Clinical Sciences, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
Zhou
Min
M
Croucher
Peter I
PI
D051722:ADAM Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D054513:Group IV Phospholipases A2; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D039641:Integrin beta Chains / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D039564:Integrin alphaV; D039641:Integrin beta Chains; D015850:Interleukin-6; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C084344:integrin beta5; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D051722:ADAM Proteins; C098339:ADAM9 protein, human