Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo.
Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction. These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation. Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success. Stimulating osteoblastic bone formation to promote repair is a novel alternative approach. We show that a soluble activin receptor type IIA fusion protein (ActRIIA.muFc) stimulates osteoblastogenesis (p < .01), promotes bone formation (p < .01) and increases bone mass in vivo (p < .001). We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption (p < .05) and suppression of bone formation (p < .01). ActRIIA.muFc treatment stimulates osteoblastogenesis (p < .01), prevents myeloma-induced suppression of bone formation (p < .05), blocks the development of osteolytic bone lesions (p < .05), and increases survival (p < .05). We also show, in a murine model of breast cancer bone metastasis, that ActRIIA.muFc again prevents bone destruction (p < .001) and inhibits bone metastases (p < .05). These findings show that stimulating osteoblastic bone formation with ActRIIA.muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer.
Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom.
Andrew D
AD
Chantry
Debby
D
Heath
Aaron W
AW
Mulivor
Scott
S
Pearsall
Marc
M
Baud'huin
Les
L
Coulton
Holly
H
Evans
Nicole
N
Abdul
Eric D
ED
Werner
Mary L
ML
Bouxsein
Michelle L
ML
Key
Jasbir
J
Seehra
Timothy R
TR
Arnett
Karin
K
Vanderkerken
Peter
P
Croucher
D028341:Activins / Q000378:metabolism*; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications* / Q000473:pathology / Q000503:physiopathology / Q000556:secondary; D001862:Bone Resorption / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002113:Calcification, Physiologic / Q000187:drug effects; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D009368:Neoplasm Transplantation; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000097:blood / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control; D010266:Paraproteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects
D010266:Paraproteins; D011993:Recombinant Fusion Proteins; C422405:activin A; D028341:Activins