Abstract
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.
Highlights
Skeletal metastasis is a common clinical manifestation in advanced-stage patients suffering from prostate cancer (CaP) [1,2] and mammary cancer (CaM) [3]
We investigated whether short hairpin RNA-mediated noggin suppression in PC-3 cells, constitutively secreting this protein [17], could preserve bone formation in the osteolytic lesions
Silencing of Noggin mRNA and protein expression in the PC-3/firefly luciferase (Fluc) Cell clone by short hairpin RNA (shRNA)
Summary
Skeletal metastasis is a common clinical manifestation in advanced-stage patients suffering from prostate cancer (CaP) [1,2] and mammary cancer (CaM) [3]. Tumor cells perturb the physiological bone homeostasis controlled by osteoblasts and osteoclasts. CaM bone metastases tend to elicit an osteolytic response, whereas CaP metastases are prevalently associated with an osteosclerotic reaction [5,6]. Both types of lesions compromise the skeletal integrity and eventually lead to pathological fractures. The prevailing concept indicates that cancer cells secrete an excess of paracrine factors stimulating directly or indirectly osteoclast or osteoblast recruitment, thereby leading to unbalanced excess of bone resorption or formation, respectively [7,8]
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