TY - JOUR
T1 - Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease
AU - Vallet, Sonia
AU - Mukherjee, Siddhartha
AU - Vaghela, Nileshwari
AU - Hideshima, Teru
AU - Fulciniti, Mariateresa
AU - Pozzi, Samantha
AU - Santo, Loredana
AU - Cirstea, Diana
AU - Patel, Kishan
AU - Sohani, Aliyah R.
AU - Guimaraes, Alex
AU - Xie, Wanling
AU - Chauhan, Dharminder
AU - Schoonmaker, Jesse A.
AU - Attar, Eyal
AU - Churchill, Michael
AU - Weller, Edie
AU - Munshi, Nikhil
AU - Seehra, Jasbir S.
AU - Weissleder, Ralph
AU - Anderson, Kenneth C.
AU - Scadden, David T.
AU - Raje, Noopur
PY - 2010/3/16
Y1 - 2010/3/16
N2 - 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.
AB - 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.
KW - Osteoblasts
KW - Osteoclasts
KW - Tumor niche
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UR - http://www.scopus.com/inward/citedby.url?scp=77950438331&partnerID=8YFLogxK
U2 - 10.1073/pnas.0911929107
DO - 10.1073/pnas.0911929107
M3 - Article
C2 - 20194748
AN - SCOPUS:77950438331
SN - 0027-8424
VL - 107
SP - 5124
EP - 5129
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -