AbstractUnderstanding 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.

Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease / S., Vallet; S., Mukherjee; N., Vaghela; T., Hideshima; M., Fulciniti; Pozzi, Samantha; L., Santo; D., Cirstea; K., Patel; A. R., Sohani; A., Guimaraes; W., Xie; D., Chauhan; J. A., Schoonmaker; E., Attar; M., Churchill; E., Weller; N., Munshi; J. S., Seehra; R., Weissleder; K. C., Anderson; D. T., Scadden; N., Raje. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - ELETTRONICO. - 107:11(2010), pp. 5124-5129. [10.1073/pnas.0911929107]

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

POZZI, Samantha;
2010

Abstract

AbstractUnderstanding 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.
2010
107
11
5124
5129
Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease / S., Vallet; S., Mukherjee; N., Vaghela; T., Hideshima; M., Fulciniti; Pozzi, Samantha; L., Santo; D., Cirstea; K., Patel; A. R., Sohani; A., Guimaraes; W., Xie; D., Chauhan; J. A., Schoonmaker; E., Attar; M., Churchill; E., Weller; N., Munshi; J. S., Seehra; R., Weissleder; K. C., Anderson; D. T., Scadden; N., Raje. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - ELETTRONICO. - 107:11(2010), pp. 5124-5129. [10.1073/pnas.0911929107]
S., Vallet; S., Mukherjee; N., Vaghela; T., Hideshima; M., Fulciniti; Pozzi, Samantha; L., Santo; D., Cirstea; K., Patel; A. R., Sohani; A., Guimaraes...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/712598
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