1. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease.
- Author
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Vallet, Sonia, Mukherjee, Siddhartha, Vaghela, Nileshwari, Hideshima, Teru, Fulciniti, Mariateresa, Pozzi, Samantha, Santo, Loredana, Cirstea, Diana, Patel, Kishan, Sohani, Aliyah R., Guimaraes, Alex, Wanling Xie, Chauhan, Dharminder, Schoonmaker, Jesse A., Attar, Eyal, Churchill, Michael, Weller, Edie, Munshi, Nikhil, Seehra, Jasbir S., and Weissleder, Ralph
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ACTIVIN , *GLYCOPROTEINS , *MYELOMA proteins , *BONE resorption , *BONE marrow - Abstract
Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-β 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 iNK 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. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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