The role of the BMP signaling antagonist noggin in the development of prostate cancer osteolytic bone metastasis.
Members of the BMP and Wnt protein families play a relevant role in physiologic and pathologic bone turnover. Extracellular antagonists are crucial for the modulation of their activity. Lack of expression of the BMP antagonist noggin by osteoinductive, carcinoma-derived cell lines is a determinant of the osteoblast response induced by their bone metastases. In contrast, osteolytic, carcinoma-derived cell lines express noggin constitutively. We hypothesized that cancer cell-derived noggin may contribute to the pathogenesis of osteolytic bone metastasis of solid cancers by repressing bone formation. Intra-osseous xenografts of PC-3 prostate cancer cells induced osteolytic lesions characterized not only by enhanced osteoclast-mediated bone resorption, but also by decreased osteoblast-mediated bone formation. Therefore, in this model, uncoupling of the bone remodeling process contributes to osteolysis. Bone formation was preserved in the osteolytic lesions induced by noggin-silenced PC-3 cells, suggesting that cancer cell-derived noggin interferes with physiologic bone coupling. Furthermore, intra-osseous tumor growth of noggin-silenced PC-3 cells was limited, most probably as a result of the persisting osteoblast activity. This investigation provides new evidence for a model of osteolytic bone metastasis where constitutive secretion of noggin by cancer cells mediates inhibition of bone formation, thereby preventing repair of osteolytic lesions generated by an excess of osteoclast-mediated bone resorption. Therefore, noggin suppression may be a novel strategy for the treatment of osteolytic bone metastases.
Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
Chiara
C
Secondini
Antoinette
A
Wetterwald
Ruth
R
Schwaninger
George N
GN
Thalmann
Marco G
MG
Cecchini
D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D001859:Bone Neoplasms / Q000209:etiology* / Q000556:secondary; D016723:Bone Remodeling; D001862:Bone Resorption; D002352:Carrier Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D010006:Osteoblasts / Q000473:pathology; D010014:Osteolysis / Q000209:etiology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D015398:Signal Transduction; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D000099176:Noggin Protein
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