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Growth/differentiation factor-15 inhibits differentiation into osteoclasts--a novel factor involved in control of osteoclast differentiation
P. Vaňhara, E. Lincovaá A. Kozubík, P. Jurdic, K. Souček, J. Šmarda
Language English Country Great Britain
Document type Research Support, Non-U.S. Gov't
Grant support
NS9875
MZ0
CEP Register
Digital library NLK
Full text - Article
Source
- MeSH
- Cell Differentiation drug effects MeSH
- Cell Line MeSH
- Time Factors MeSH
- Macrophage Colony-Stimulating Factor pharmacology MeSH
- Femur cytology MeSH
- Mice, Inbred Strains MeSH
- Isoenzymes metabolism MeSH
- Calcitriol pharmacology MeSH
- Carbonic Anhydrase II antagonists & inhibitors MeSH
- Cathepsin K antagonists & inhibitors genetics MeSH
- Culture Media, Conditioned pharmacology MeSH
- Acid Phosphatase metabolism MeSH
- Humans MeSH
- RANK Ligand pharmacology MeSH
- Macrophages cytology MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Prostatic Neoplasms metabolism MeSH
- NF-kappa B antagonists & inhibitors MeSH
- Osteoclasts metabolism drug effects MeSH
- Proto-Oncogene Proteins c-fos antagonists & inhibitors MeSH
- Growth Differentiation Factor 15 pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
Survival and capability of cancer cells to form metastases fundamentally depend on interactions with their microenvironment. Secondary tumors originating from prostate carcinomas affect remodeling of bone tissue and can induce both osteolytic and osteocondensing lesions. However, particular molecular mechanisms responsible for selective homing and activity of cancer cells in bone microenvironment have not been clarified yet. Growth/differentiation factor-15 (GDF-15), a distant member of the TGF-beta protein family, has recently been associated with many human cancers, including prostate. We show that both pure GDF-15 and the GDF-15-containing growth medium of 1,25(OH)(2)-vitamin D(3)-treated prostate adenocarcinoma LNCaP cells suppress formation of mature osteoclasts differentiated from RAW264.7 macrophages and bone-marrow precursors by M-CSF/RANKL in a dose-dependent manner. GDF-15 inhibits expression of c-Fos and activity of NFkappaB by delayed degradation of IkappaB. Moreover, GDF-15 inhibits expression of carbonic anhydrase II and cathepsin K, key osteoclast enzymes, and induces changes in SMAD and p38 signaling. The lack of functional osteoclasts can contribute to accumulation of bone matrix by reduction of bone resorption. These results unveil new role of GDF-15 in modulation of osteoclast differentiation and possibly in therapy of bone metastases.
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- $a Growth/differentiation factor-15 inhibits differentiation into osteoclasts--a novel factor involved in control of osteoclast differentiation $c P. Vaňhara, E. Lincovaá A. Kozubík, P. Jurdic, K. Souček, J. Šmarda
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- $a Survival and capability of cancer cells to form metastases fundamentally depend on interactions with their microenvironment. Secondary tumors originating from prostate carcinomas affect remodeling of bone tissue and can induce both osteolytic and osteocondensing lesions. However, particular molecular mechanisms responsible for selective homing and activity of cancer cells in bone microenvironment have not been clarified yet. Growth/differentiation factor-15 (GDF-15), a distant member of the TGF-beta protein family, has recently been associated with many human cancers, including prostate. We show that both pure GDF-15 and the GDF-15-containing growth medium of 1,25(OH)(2)-vitamin D(3)-treated prostate adenocarcinoma LNCaP cells suppress formation of mature osteoclasts differentiated from RAW264.7 macrophages and bone-marrow precursors by M-CSF/RANKL in a dose-dependent manner. GDF-15 inhibits expression of c-Fos and activity of NFkappaB by delayed degradation of IkappaB. Moreover, GDF-15 inhibits expression of carbonic anhydrase II and cathepsin K, key osteoclast enzymes, and induces changes in SMAD and p38 signaling. The lack of functional osteoclasts can contribute to accumulation of bone matrix by reduction of bone resorption. These results unveil new role of GDF-15 in modulation of osteoclast differentiation and possibly in therapy of bone metastases.
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