Vallet, SoniaMukherjee, SiddharthaVaghela, NileshwariHideshima, TeruFulciniti, MariateresaPozzi, SamanthaSanto, LoredanaCirstea, DianaPatel, KishanSohani, Aliyah R.Guimaraes, AlexXie, WanlingChauhan, DharminderSchoonmaker, Jesse A.Attar, EyalChurchill, MichaelWeller, EdieMunshi, NikhilSeehra, Jasbir S.Weissleder, RalphAnderson, Kenneth C.Scadden, David T.Raje, Noopur2019-09-212010Vallet, S., S. Mukherjee, N. Vaghela, T. Hideshima, M. Fulciniti, S. Pozzi, L. Santo, et al. 2010. “Activin A Promotes Multiple Myeloma-Induced Osteolysis and Is a Promising Target for Myeloma Bone Disease.” Proceedings of the National Academy of Sciences 107 (11): 5124–29. https://doi.org/10.1073/pnas.0911929107.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41384298Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-beta family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distalless homeobox-5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.en-USJournal Article2019-09-2110.1073/pnas.0911929107