Activin a promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease
Sohani, Aliyah R.
Schoonmaker, Jesse A.
Seehra, Jasbir S.
Anderson, Kenneth C.
Scadden, David T.
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CitationVallet, 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.
AbstractUnderstanding 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.
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