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Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

2010; Oxford University Press; Volume: 25; Issue: 12 Linguagem: Inglês

10.1002/jbmr.142

1523-4681

Andrew Chantry, Debby Heath, Aaron W. Mulivor, Scott Pearsall, Marc Baud’huin, Les Coulton, Holly Evans, Nicole Abdul, Eric D. Werner, Mary Bouxsein, Michelle L. Key, Jasbir Seehra, Timothy R. Arnett, Karin Vanderkerken, Peter I. Croucher,

Orthopaedic implants and arthroplasty

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.