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Inhibiting activin‐A signaling stimulates bone formation and prevents cancer‐induced bone destruction in vivo
Author(s) -
Chantry Andrew D,
Heath Debby,
Mulivor Aaron W,
Pearsall Scott,
Baud'huin Marc,
Coulton Les,
Evans Holly,
Abdul Nicole,
Werner Eric D,
Bouxsein Mary L,
Key Michelle L,
Seehra Jasbir,
Arnett Timothy R,
Vanderkerken Karin,
Croucher Peter
Publication year - 2010
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.142
Subject(s) - in vivo , cancer research , signal transduction , activin type 2 receptors , bone formation , microbiology and biotechnology , chemistry , endocrinology , medicine , tgf beta signaling pathway , biology , transforming growth factor
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. © 2010 American Society for Bone and Mineral Research.