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Receptor-Activator of Nuclear KappaB Ligand Expression as a New Therapeutic Target in Primary Bone Tumors.

Yamagishi T, Kawashima H, Ogose A, Ariizumi T, Sasaki T, Hatano H, Hotta T, Endo N - PLoS ONE (2016)

Bottom Line: It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone.High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma.RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia.

View Article: PubMed Central - PubMed

Affiliation: Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

ABSTRACT
The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts.

No MeSH data available.


Related in: MedlinePlus

Hematoxylin-eosin and RANKL stains on FD.(6a) Stromal spindle-shaped cells and trabecular of woven bone without osteoblastic rim were observed. (6b) RANKL-positive stromal cells were detected.
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pone.0154680.g006: Hematoxylin-eosin and RANKL stains on FD.(6a) Stromal spindle-shaped cells and trabecular of woven bone without osteoblastic rim were observed. (6b) RANKL-positive stromal cells were detected.

Mentions: Six RANKL-positive cases were detected: five cases of GCTB and one case of fibrous dysplasia. RANKL-positive stromal cells were detected in five cases of GCTB (Fig 5A and 5B), but not in the other 13 cases of GCTB. None of the five RANKL-positive cases had decalcified tissue sections, and there were no RANKL-positive cells in the 11 cases with decalcified tissue sections. RANKL-positive cells were detected in one fibrous dysplasia case (Fig 6A and 6B). On the other hand, no RANKL-positive cells were detected in multiple myeloma, bone metastases, osteosarcoma, Ewing’ sarcoma, or ABC, which expressed RANKL mRNA (Fig 7A and 7B). RANKL expression could not be assessed in chordoma or chondrosarcoma, which are composed of myxoid parts, because these tissue sections were detached from slides by heat-induced antigen retrieval.


Receptor-Activator of Nuclear KappaB Ligand Expression as a New Therapeutic Target in Primary Bone Tumors.

Yamagishi T, Kawashima H, Ogose A, Ariizumi T, Sasaki T, Hatano H, Hotta T, Endo N - PLoS ONE (2016)

Hematoxylin-eosin and RANKL stains on FD.(6a) Stromal spindle-shaped cells and trabecular of woven bone without osteoblastic rim were observed. (6b) RANKL-positive stromal cells were detected.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4862691&req=5

pone.0154680.g006: Hematoxylin-eosin and RANKL stains on FD.(6a) Stromal spindle-shaped cells and trabecular of woven bone without osteoblastic rim were observed. (6b) RANKL-positive stromal cells were detected.
Mentions: Six RANKL-positive cases were detected: five cases of GCTB and one case of fibrous dysplasia. RANKL-positive stromal cells were detected in five cases of GCTB (Fig 5A and 5B), but not in the other 13 cases of GCTB. None of the five RANKL-positive cases had decalcified tissue sections, and there were no RANKL-positive cells in the 11 cases with decalcified tissue sections. RANKL-positive cells were detected in one fibrous dysplasia case (Fig 6A and 6B). On the other hand, no RANKL-positive cells were detected in multiple myeloma, bone metastases, osteosarcoma, Ewing’ sarcoma, or ABC, which expressed RANKL mRNA (Fig 7A and 7B). RANKL expression could not be assessed in chordoma or chondrosarcoma, which are composed of myxoid parts, because these tissue sections were detached from slides by heat-induced antigen retrieval.

Bottom Line: It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone.High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma.RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia.

View Article: PubMed Central - PubMed

Affiliation: Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

ABSTRACT
The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts.

No MeSH data available.


Related in: MedlinePlus