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 Weissleder; Kenneth C. Anderson; David T. Scadden; Noopur Raje

doi:10.1073/pnas.0911929107

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

196 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 language	English
Pages (from-to)	5124-5129
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	107
Issue number	11
DOIs	https://doi.org/10.1073/pnas.0911929107
Publication status	Published - 16 Mar 2010
Externally published	Yes

Keywords

Osteoblasts
Osteoclasts
Tumor niche

ASJC Scopus subject areas

Multidisciplinary

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10.1073/pnas.0911929107

Cite this

Vallet, S., Mukherjee, S., Vaghela, N., Hideshima, T., Fulciniti, M., Pozzi, S., Santo, L., Cirstea, D., Patel, K., Sohani, A. R., Guimaraes, A., Xie, W., Chauhan, D., Schoonmaker, J. A., Attar, E., Churchill, M., Weller, E., Munshi, N., Seehra, J. S., ... Raje, N. (2010). Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proceedings of the National Academy of Sciences of the United States of America, 107(11), 5124-5129. https://doi.org/10.1073/pnas.0911929107

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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.",

keywords = "Osteoblasts, Osteoclasts, Tumor niche",

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

year = "2010",

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doi = "10.1073/pnas.0911929107",

language = "English",

volume = "107",

pages = "5124--5129",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Vallet, S, Mukherjee, S, Vaghela, N, Hideshima, T, Fulciniti, M, Pozzi, S, Santo, L, Cirstea, D, Patel, K, Sohani, AR, Guimaraes, A, Xie, W, Chauhan, D, Schoonmaker, JA, Attar, E, Churchill, M, Weller, E, Munshi, N, Seehra, JS, Weissleder, R, Anderson, KC, Scadden, DT & Raje, N 2010, 'Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 11, pp. 5124-5129. https://doi.org/10.1073/pnas.0911929107

Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. / Vallet, Sonia; Mukherjee, Siddhartha; Vaghela, Nileshwari et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 11, 16.03.2010, p. 5124-5129.

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

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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U2 - 10.1073/pnas.0911929107

DO - 10.1073/pnas.0911929107

M3 - Journal 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 -

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

Abstract

Keywords

ASJC Scopus subject areas

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