title: Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease.
abstract: 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.
authors.affiliation: Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Vallet
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Nileshwari
authors.initials: N
authors.lastname: Vaghela
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.forename: Samantha
authors.initials: S
authors.lastname: Pozzi
authors.forename: Loredana
authors.initials: L
authors.lastname: Santo
authors.forename: Diana
authors.initials: D
authors.lastname: Cirstea
authors.forename: Kishan
authors.initials: K
authors.lastname: Patel
authors.forename: Aliyah R
authors.initials: AR
authors.lastname: Sohani
authors.forename: Alex
authors.initials: A
authors.lastname: Guimaraes
authors.forename: Wanling
authors.initials: W
authors.lastname: Xie
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Schoonmaker
authors.forename: Eyal
authors.initials: E
authors.lastname: Attar
authors.forename: Michael
authors.initials: M
authors.lastname: Churchill
authors.forename: Edie
authors.initials: E
authors.lastname: Weller
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.forename: Jasbir S
authors.initials: JS
authors.lastname: Seehra
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
mesh_terms: 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
chemical_list: 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