Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease

Sonia Vallet, Siddhartha Mukherjee, Nileshwari Vaghela, Teru Hideshima, Mariateresa Fulciniti, Samantha Pozzi, Loredana Santo, Diana Cirstea, Kishan Patel, Aliyah R. Sohani, Alex Guimaraes, Wanling Xie, Dharminder Chauhan, Jesse A. Schoonmaker, Eyal Attar, Michael Churchill, Edie Weller, Nikhil Munshi, Jasbir S. Seehra, Ralph WeisslederKenneth C. Anderson, David T. Scadden, Noopur Raje*

*Corresponding author for this work

Research output: Journal article (peer-reviewed)Journal article

195 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)5124-5129
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number11
DOIs
Publication statusPublished - 16 Mar 2010
Externally publishedYes

Keywords

  • Osteoblasts
  • Osteoclasts
  • Tumor niche

ASJC Scopus subject areas

  • Multidisciplinary

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