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The role of the BMP signaling antagonist noggin in the development of prostate cancer osteolytic bone metastasis.

Secondini C, Wetterwald A, Schwaninger R, Thalmann GN, Cecchini MG - PLoS ONE (2011)

Bottom Line: Extracellular antagonists are crucial for the modulation of their activity.In contrast, osteolytic, carcinoma-derived cell lines express noggin constitutively.Furthermore, intra-osseous tumor growth of noggin-silenced PC-3 cells was limited, most probably as a result of the persisting osteoblast activity.

View Article: PubMed Central - PubMed

Affiliation: Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.

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.

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Noggin silencing normalizes the bone histomorphometric indexes of bone formation and resorption in osteolytic lesions.A. Number of osteoclasts (N.Oc/BS; /mm, +/− SD) on the endosteal surface in trabecular and cortical bone of sham-operated tibiae or on residual bone adjacent to cancer cells of tibiae xenografted with PC-3/Fluc, mock and Nog-KD clones. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus sham, and mock clones versus Nog-KD 17; **P<0.01, Nog-KD 17 versus PC-3/Fluc, and Nog-KD 14 versus PC-3/Fluc and mock clones. B. Number of osteoblasts (N.Ob/BS; /mm, +/− SD) on the endosteal surface in trabecular and cortical bone of sham-operated tibiae or on residual bone adjacent to cancer cells of tibiae xenografted with PC-3/Fluc, mock and Nog-KD clones. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus Nog-KD clones, and mock 4 versus sham; **P<0.01, sham versus PC-3/Fluc and mock 5; *P<0.05, Nog-KD 14 versus sham. C. Percentage of endosteal surface in cortical and trabecular bone occupied by osteoclasts (Oc.S/BS; %, +/− SD) in sham-operated and cancer cell-xenografted tibiae. n = 6–7 animals for each experimental group. ***P<0.001, mock clones versus sham and Nog-KD clones, and PC-3/Fluc versus sham and Nog-KD 17; **P<0.01, Nog-KD 14 versus PC-3/Fluc. D. Percentage of endosteal surface in cortical and trabecular bone occupied by osteoblasts (Ob.S/BS; %, +/− SD) in sham-operated and cancer cell-xenografted tibiae. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus sham and Nog-KD clones.
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pone-0016078-g005: Noggin silencing normalizes the bone histomorphometric indexes of bone formation and resorption in osteolytic lesions.A. Number of osteoclasts (N.Oc/BS; /mm, +/− SD) on the endosteal surface in trabecular and cortical bone of sham-operated tibiae or on residual bone adjacent to cancer cells of tibiae xenografted with PC-3/Fluc, mock and Nog-KD clones. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus sham, and mock clones versus Nog-KD 17; **P<0.01, Nog-KD 17 versus PC-3/Fluc, and Nog-KD 14 versus PC-3/Fluc and mock clones. B. Number of osteoblasts (N.Ob/BS; /mm, +/− SD) on the endosteal surface in trabecular and cortical bone of sham-operated tibiae or on residual bone adjacent to cancer cells of tibiae xenografted with PC-3/Fluc, mock and Nog-KD clones. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus Nog-KD clones, and mock 4 versus sham; **P<0.01, sham versus PC-3/Fluc and mock 5; *P<0.05, Nog-KD 14 versus sham. C. Percentage of endosteal surface in cortical and trabecular bone occupied by osteoclasts (Oc.S/BS; %, +/− SD) in sham-operated and cancer cell-xenografted tibiae. n = 6–7 animals for each experimental group. ***P<0.001, mock clones versus sham and Nog-KD clones, and PC-3/Fluc versus sham and Nog-KD 17; **P<0.01, Nog-KD 14 versus PC-3/Fluc. D. Percentage of endosteal surface in cortical and trabecular bone occupied by osteoblasts (Ob.S/BS; %, +/− SD) in sham-operated and cancer cell-xenografted tibiae. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus sham and Nog-KD clones.

Mentions: In the tibiae xenografted with PC-3/Fluc and mock clones there was a significant increase in osteoclast number and percentage of surface covered by osteoclasts, as compared to the sham-operated tibiae (Figure 5A and C). This was accompanied by a significant decrease in osteoblast number and percentage of surface covered by active osteoblasts (Figure 5B and D).


The role of the BMP signaling antagonist noggin in the development of prostate cancer osteolytic bone metastasis.

Secondini C, Wetterwald A, Schwaninger R, Thalmann GN, Cecchini MG - PLoS ONE (2011)

Noggin silencing normalizes the bone histomorphometric indexes of bone formation and resorption in osteolytic lesions.A. Number of osteoclasts (N.Oc/BS; /mm, +/− SD) on the endosteal surface in trabecular and cortical bone of sham-operated tibiae or on residual bone adjacent to cancer cells of tibiae xenografted with PC-3/Fluc, mock and Nog-KD clones. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus sham, and mock clones versus Nog-KD 17; **P<0.01, Nog-KD 17 versus PC-3/Fluc, and Nog-KD 14 versus PC-3/Fluc and mock clones. B. Number of osteoblasts (N.Ob/BS; /mm, +/− SD) on the endosteal surface in trabecular and cortical bone of sham-operated tibiae or on residual bone adjacent to cancer cells of tibiae xenografted with PC-3/Fluc, mock and Nog-KD clones. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus Nog-KD clones, and mock 4 versus sham; **P<0.01, sham versus PC-3/Fluc and mock 5; *P<0.05, Nog-KD 14 versus sham. C. Percentage of endosteal surface in cortical and trabecular bone occupied by osteoclasts (Oc.S/BS; %, +/− SD) in sham-operated and cancer cell-xenografted tibiae. n = 6–7 animals for each experimental group. ***P<0.001, mock clones versus sham and Nog-KD clones, and PC-3/Fluc versus sham and Nog-KD 17; **P<0.01, Nog-KD 14 versus PC-3/Fluc. D. Percentage of endosteal surface in cortical and trabecular bone occupied by osteoblasts (Ob.S/BS; %, +/− SD) in sham-operated and cancer cell-xenografted tibiae. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus sham and Nog-KD clones.
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Related In: Results  -  Collection

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pone-0016078-g005: Noggin silencing normalizes the bone histomorphometric indexes of bone formation and resorption in osteolytic lesions.A. Number of osteoclasts (N.Oc/BS; /mm, +/− SD) on the endosteal surface in trabecular and cortical bone of sham-operated tibiae or on residual bone adjacent to cancer cells of tibiae xenografted with PC-3/Fluc, mock and Nog-KD clones. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus sham, and mock clones versus Nog-KD 17; **P<0.01, Nog-KD 17 versus PC-3/Fluc, and Nog-KD 14 versus PC-3/Fluc and mock clones. B. Number of osteoblasts (N.Ob/BS; /mm, +/− SD) on the endosteal surface in trabecular and cortical bone of sham-operated tibiae or on residual bone adjacent to cancer cells of tibiae xenografted with PC-3/Fluc, mock and Nog-KD clones. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus Nog-KD clones, and mock 4 versus sham; **P<0.01, sham versus PC-3/Fluc and mock 5; *P<0.05, Nog-KD 14 versus sham. C. Percentage of endosteal surface in cortical and trabecular bone occupied by osteoclasts (Oc.S/BS; %, +/− SD) in sham-operated and cancer cell-xenografted tibiae. n = 6–7 animals for each experimental group. ***P<0.001, mock clones versus sham and Nog-KD clones, and PC-3/Fluc versus sham and Nog-KD 17; **P<0.01, Nog-KD 14 versus PC-3/Fluc. D. Percentage of endosteal surface in cortical and trabecular bone occupied by osteoblasts (Ob.S/BS; %, +/− SD) in sham-operated and cancer cell-xenografted tibiae. n = 6–7 animals for each experimental group. ***P<0.001, PC-3/Fluc and mock clones versus sham and Nog-KD clones.
Mentions: In the tibiae xenografted with PC-3/Fluc and mock clones there was a significant increase in osteoclast number and percentage of surface covered by osteoclasts, as compared to the sham-operated tibiae (Figure 5A and C). This was accompanied by a significant decrease in osteoblast number and percentage of surface covered by active osteoblasts (Figure 5B and D).

Bottom Line: Extracellular antagonists are crucial for the modulation of their activity.In contrast, osteolytic, carcinoma-derived cell lines express noggin constitutively.Furthermore, intra-osseous tumor growth of noggin-silenced PC-3 cells was limited, most probably as a result of the persisting osteoblast activity.

View Article: PubMed Central - PubMed

Affiliation: Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.

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.

Show MeSH
Related in: MedlinePlus