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Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis.

Ohshiba T, Miyaura C, Inada M, Ito A - Br. J. Cancer (2003)

Bottom Line: The separation of MDA-231 from the calvaria using filter insert showed decreased bone resorption, suggesting that cell-to-cell interaction is essential for cancer-induced bone resorption.Adding MDA-231 cells to bone marrow cultures markedly induced osteoclast formation, and the expression of RANKL in osteoblasts was enhanced by contact with the cell surface of MDA-231 cells.These results indicate that RANKL-induced osteoclast formation and MMP-dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan.

ABSTRACT
Bone metastasis of breast cancer induces severe osteolysis with increased bone resorption. Osteoclast differentiation regulated by the receptor activator of NF-kappaB ligand (RANKL) in osteoblasts and matrix degradation induced by matrix metalloproteinases (MMPs) are thought to be involved in the process of bone resorption. When nude mice were inoculated with human breast cancer cells, MDA-MB-231(MDA-231), numerous osteoclasts resorbed bone and the degradation of the bone matrix markedly progressed in the femur and tibia with metastasis of the MDA-231 tumour. The expression of RANKL, MMP-13 and membrane-type 1-MMP mRNA was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, MDA-231 markedly induced bone resorption measured by calcium release from the calvaria, and the expression of RANKL, MMP-2 and MMP-13 was elevated in the calvaria after the coculture. The separation of MDA-231 from the calvaria using filter insert showed decreased bone resorption, suggesting that cell-to-cell interaction is essential for cancer-induced bone resorption. Adding MDA-231 cells to bone marrow cultures markedly induced osteoclast formation, and the expression of RANKL in osteoblasts was enhanced by contact with the cell surface of MDA-231 cells. These results indicate that RANKL-induced osteoclast formation and MMP-dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer.

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Representative radiographs and histological sections of osteolytic lesions in the hindlimbs of nude mice injected with MDA-231 cells. (A, B) Soft X-ray analyses of the hindlimbs of control mouse injected with PBS (A) and mouse injected with MDA-231 cells (B). Arrowhead indicates the osteolytic lesion because of metastasis in the tibia. (C, D) HE staining of histological sections of tibia collected from the mice shown in panels A and B, respectively. In the control section (C), bone marrow cells (BM) were normal and the cortical bone (CB) surface was smooth. In the metastasised section (D), tumour filled the bone marrow cavity and replaced the cellular elements. Arrows indicate osteoclasts (OC) on the cortical surface. (E, F) TRAP staining of the serial sections of panels C and D, respectively. In the metastasized section (F), TRAP-positive osteoclasts were aligned on the cortical surface.
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fig1: Representative radiographs and histological sections of osteolytic lesions in the hindlimbs of nude mice injected with MDA-231 cells. (A, B) Soft X-ray analyses of the hindlimbs of control mouse injected with PBS (A) and mouse injected with MDA-231 cells (B). Arrowhead indicates the osteolytic lesion because of metastasis in the tibia. (C, D) HE staining of histological sections of tibia collected from the mice shown in panels A and B, respectively. In the control section (C), bone marrow cells (BM) were normal and the cortical bone (CB) surface was smooth. In the metastasised section (D), tumour filled the bone marrow cavity and replaced the cellular elements. Arrows indicate osteoclasts (OC) on the cortical surface. (E, F) TRAP staining of the serial sections of panels C and D, respectively. In the metastasized section (F), TRAP-positive osteoclasts were aligned on the cortical surface.

Mentions: We first performed histological analyses in bone with metastasis of breast cancer cells, MDA-231 cells, using a typical in vivo model. Radiographic examination demonstrated the development of metastatic osteolytic lesions in the femur and tibiae 6 weeks after the injection of MDA-231 cells in nude mice (Figure 1Figure 1


Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis.

Ohshiba T, Miyaura C, Inada M, Ito A - Br. J. Cancer (2003)

Representative radiographs and histological sections of osteolytic lesions in the hindlimbs of nude mice injected with MDA-231 cells. (A, B) Soft X-ray analyses of the hindlimbs of control mouse injected with PBS (A) and mouse injected with MDA-231 cells (B). Arrowhead indicates the osteolytic lesion because of metastasis in the tibia. (C, D) HE staining of histological sections of tibia collected from the mice shown in panels A and B, respectively. In the control section (C), bone marrow cells (BM) were normal and the cortical bone (CB) surface was smooth. In the metastasised section (D), tumour filled the bone marrow cavity and replaced the cellular elements. Arrows indicate osteoclasts (OC) on the cortical surface. (E, F) TRAP staining of the serial sections of panels C and D, respectively. In the metastasized section (F), TRAP-positive osteoclasts were aligned on the cortical surface.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747560&req=5

fig1: Representative radiographs and histological sections of osteolytic lesions in the hindlimbs of nude mice injected with MDA-231 cells. (A, B) Soft X-ray analyses of the hindlimbs of control mouse injected with PBS (A) and mouse injected with MDA-231 cells (B). Arrowhead indicates the osteolytic lesion because of metastasis in the tibia. (C, D) HE staining of histological sections of tibia collected from the mice shown in panels A and B, respectively. In the control section (C), bone marrow cells (BM) were normal and the cortical bone (CB) surface was smooth. In the metastasised section (D), tumour filled the bone marrow cavity and replaced the cellular elements. Arrows indicate osteoclasts (OC) on the cortical surface. (E, F) TRAP staining of the serial sections of panels C and D, respectively. In the metastasized section (F), TRAP-positive osteoclasts were aligned on the cortical surface.
Mentions: We first performed histological analyses in bone with metastasis of breast cancer cells, MDA-231 cells, using a typical in vivo model. Radiographic examination demonstrated the development of metastatic osteolytic lesions in the femur and tibiae 6 weeks after the injection of MDA-231 cells in nude mice (Figure 1Figure 1

Bottom Line: The separation of MDA-231 from the calvaria using filter insert showed decreased bone resorption, suggesting that cell-to-cell interaction is essential for cancer-induced bone resorption.Adding MDA-231 cells to bone marrow cultures markedly induced osteoclast formation, and the expression of RANKL in osteoblasts was enhanced by contact with the cell surface of MDA-231 cells.These results indicate that RANKL-induced osteoclast formation and MMP-dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan.

ABSTRACT
Bone metastasis of breast cancer induces severe osteolysis with increased bone resorption. Osteoclast differentiation regulated by the receptor activator of NF-kappaB ligand (RANKL) in osteoblasts and matrix degradation induced by matrix metalloproteinases (MMPs) are thought to be involved in the process of bone resorption. When nude mice were inoculated with human breast cancer cells, MDA-MB-231(MDA-231), numerous osteoclasts resorbed bone and the degradation of the bone matrix markedly progressed in the femur and tibia with metastasis of the MDA-231 tumour. The expression of RANKL, MMP-13 and membrane-type 1-MMP mRNA was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, MDA-231 markedly induced bone resorption measured by calcium release from the calvaria, and the expression of RANKL, MMP-2 and MMP-13 was elevated in the calvaria after the coculture. The separation of MDA-231 from the calvaria using filter insert showed decreased bone resorption, suggesting that cell-to-cell interaction is essential for cancer-induced bone resorption. Adding MDA-231 cells to bone marrow cultures markedly induced osteoclast formation, and the expression of RANKL in osteoblasts was enhanced by contact with the cell surface of MDA-231 cells. These results indicate that RANKL-induced osteoclast formation and MMP-dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer.

Show MeSH
Related in: MedlinePlus