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

Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5124-9. doi: 10.1073/pnas.0911929107. Epub 2010 Mar 1.


Understanding 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 distal-less 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / antagonists & inhibitors
  • Activins / metabolism*
  • Animals
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Cell Differentiation
  • Cell Line, Tumor
  • Down-Regulation
  • Enzyme Activation
  • Homeodomain Proteins / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Multiple Myeloma / complications*
  • Multiple Myeloma / enzymology
  • Multiple Myeloma / pathology
  • Osteoblasts / pathology
  • Osteolysis / etiology*
  • Osteolysis / pathology
  • Receptors, Cell Surface / metabolism
  • Smad2 Protein / metabolism
  • Stromal Cells / metabolism
  • Stromal Cells / pathology


  • Dlx5 protein, mouse
  • Homeodomain Proteins
  • Receptors, Cell Surface
  • Smad2 Protein
  • Smad2 protein, mouse
  • activin A
  • Activins
  • JNK Mitogen-Activated Protein Kinases