Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease.
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.
Vallet
Sonia
S
Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Mukherjee
Siddhartha
S
Vaghela
Nileshwari
N
Hideshima
Teru
T
Fulciniti
Mariateresa
M
Pozzi
Samantha
S
Santo
Loredana
L
Cirstea
Diana
D
Patel
Kishan
K
Sohani
Aliyah R
AR
Guimaraes
Alex
A
Xie
Wanling
W
Chauhan
Dharminder
D
Schoonmaker
Jesse A
JA
Attar
Eyal
E
Churchill
Michael
M
Weller
Edie
E
Munshi
Nikhil
N
Seehra
Jasbir S
JS
Weissleder
Ralph
R
Anderson
Kenneth C
KC
Scadden
David T
DT
Raje
Noopur
N
D028341:Activins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D010006:Osteoblasts / Q000473:pathology; D010014:Osteolysis / Q000209:etiology* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
C501120:Dlx5 protein, mouse; D018398:Homeodomain Proteins; D011956:Receptors, Cell Surface; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C422405:activin A; D028341:Activins; D048031:JNK Mitogen-Activated Protein Kinases