Expression of Parathyroid Hormone (PTH)-related Peptide (PTHrP) and PTH/PTHrP Receptor in Osteoclast-like Giant Cells

Nakashima, Masahiro; Nakayama, Toshiyuki; Ohtsuru, Akira; Fukada, Eiichiro; Niino, Daisuke; Yamazumi, Kazuyuki; Naito, Shinji; Ito, Masahiro; Sekine, Ichiro

doi:10.1078/0344-0338-00359

Cited by 15 publications

(17 citation statements)

References 34 publications

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“…These results correspond with previous studies showing various responses by GCT to PTH stimulation,25–29 which implied the presence of PTH1R. The expression of PTH1R by the giant cells is in line with the results discussed earlier,39 and suggests the giant cells themselves may respond to PTHrP stimulation. Normal osteoclasts produced from peripheral blood monocytes were shown to express PTH1R and respond directly to PTH by increasing bone resorption activity 40.…”

Section: Discussionsupporting

confidence: 93%

“…Kartsogiannis et al38 examined PTHrP expression in osteoclasts and found similar results to ours, where giant cells from GCT showed the presence of PTHrP in either the cytoplasm or the nucleus, or not at all. Nakashima et al39 similarly focused on the giant cells, showing positive expression for both PTHrP and PTH1R. However, both reports incidentally reveal strong PTHrP expression by the mononuclear stromal cells.…”

Section: Discussionmentioning

confidence: 99%

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PTHrP increases RANKL expression by stromal cells from giant cell tumor of bone

Cowan

Singh

Ghert

2011

Journal Orthopaedic Research

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Giant cell tumor of bone (GCT) presents with numerous osteoclast-like multinucleated giant cells that are principally responsible for the extensive bone resorption by the tumor. Although the precise etiology of GCT remains uncertain, the accumulation of giant cells is partially due to the high expression of the receptor activator of nuclear factor-kB ligand (RANKL) from the neoplastic stromal cells. Here, we have investigated whether parathyroid hormone-related protein (PTHrP) plays a role in the pathogenesis of GCT. Immunohistochemistry results revealed PTHrP expression in the stromal cells of the tumor, and that its receptor, the parathyroid hormone type 1 receptor (PTH1R), is expressed by both the stromal cells and giant cells. PCR and Western blot analyses confirmed the expression of PTHrP and PTH1R by isolated stromal cells from five patients presenting with GCT. Treatment of GCT stromal cells with varying concentrations of PTHrP (1-34) significantly increased both RANKL gene expression and the number of multinucleated cells formed from RAW 264.7 cells in co-culture experiments, whereas inhibition of PTHrP with a neutralizing antibody decreased RANKL gene expression. These results suggest that PTHrP is expressed within GCT by the stromal cells and can contribute to the abundant RANKL expression and giant cell formation within the tumor. ß

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

PTHrP increases RANKL expression by stromal cells from giant cell tumor of bone

Cowan

Singh

Ghert

2011

Journal Orthopaedic Research

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“…The expression of PTHrP and PTHrP-receptors has also been confirmed with immunohistochemistry and western blotting in our preliminary data [10]. Our findings align with others regarding the presence of PTHrP in GCT cells [28], [29]. In the current study, both stromal cells of GCT and the classic PTHrP-secreting renal cell adenocarcinoma CRL1932 showed signs of apoptosis with cytoplasmic and nuclear shrinkage and formation of apoptotic bodies upon anti-PTHrP treatment.…”

Section: Discussionsupporting

confidence: 92%

PTHrP Induces Autocrine/Paracrine Proliferation of Bone Tumor Cells through Inhibition of Apoptosis

et al. 2011

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Giant Cell Tumor of Bone (GCT) is an aggressive skeletal tumor characterized by local bone destruction, high recurrence rates and metastatic potential. Previous work in our lab has shown that the neoplastic cell of GCT is a proliferating pre-osteoblastic stromal cell in which the transcription factor Runx2 plays a role in regulating protein expression. One of the proteins expressed by these cells is parathryroid hormone-related protein (PTHrP). The objectives of this study were to determine the role played by PTHrP in GCT of bone with a focus on cell proliferation and apoptosis. Primary stromal cell cultures from 5 patients with GCT of bone and one lung metastsis were used for cell-based experiments. Control cell lines included a renal cell carcinoma (RCC) cell line and a human fetal osteoblast cell line. Cells were exposed to optimized concentrations of a PTHrP neutralizing antibody and were analyzed with the use of cell proliferation and apoptosis assays including mitochondrial dehydrogenase assays, crystal violet assays, APO-1 ELISAs, caspase activity assays, flow cytometry and immunofluorescent immunohistochemistry. Neutralization of PTHrP in the cell environment inhibited cell proliferation in a consistent manner and induced apoptosis in the GCT stromal cells, with the exception of those obtained from a lung metastasis. Cell cycle progression was not significantly affected by PTHrP neutralization. These findings indicate that PTHrP plays an autocrine/paracrine neoplastic role in GCT by allowing the proliferating stromal cells to evade apoptosis, possibly through non-traditional caspase-independent pathways. Thus PTHrP neutralizing immunotherapy is an intriguing potential therapeutic strategy for this tumor.

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“…Consequently, only limited information is currently available concerning the cellular and subcellular localisation of the PTHR1 receptor in human tissues. These reports comprise investigations on giant cell tumours (25), chondrosarcoma (8), ameloblastoma (26), medulloblastoma (27), prostate cancer (13), breast cancer (28,29) and gastric cancer (30). To the best of our knowledge there are currently no more extensive studies involving other human tumour species and investigating different types of tumours in parallel.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical identification of the PTHR1 parathyroid hormone receptor in normal and neoplastic human tissues

Lupp

Klenk

Röcken

et al. 2010

European Journal of Endocrinology

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Background: Parathyroid hormone (PTH) is a crucial regulator of calcium homoeostasis in humans. Although it is well known that PTH acts primarily on kidney and bone, the precise cellular and subcellular sites of PTH action have not been visualised in human tissues. Method: We developed and characterised a novel anti-peptide antibody to the carboxy-terminal region of the human PTH receptor type 1 (PTHR1). Specificity of the antiserum was demonstrated by i) detection of a broad band migrating at M r 85 000-95 000 in western blots of membranes from human kidney and PTHR1-transfected cells; ii) cell surface staining of PTHR1-transfected cells; iii) translocation of PTHR1 receptor immunostaining after agonist exposure; and iv) abolition of tissue immunostaining by preadsorption of the antibody with its immunising peptide. The distribution of PTHR1 receptors was investigated in 320 human tumours and their tissues of origin. Results: In the kidney, PTHR1 receptors were predominantly detected at the basolateral plasma membrane of epithelial cells in the proximal and distal tubules but not in the thin limbs of Henle, collecting ducts or glomeruli. In bone, PTHR1 receptors were detected as discrete plasma membrane staining of osteocytes and osteoblasts, whereas osteoclasts remained unstained. In addition, PTHR1 was found in the gut and in a number of neoplastic tissues including colorectal carcinoma, prostate cancer, renal cell carcinoma and osteosarcoma. Conclusion: This is the first localisation of PTHR1 receptors in human tissues at the cellular level. The overexpression of PTHR1 receptors may provide a molecular basis for efficient targeting of human tumours with radiolabelled PTH analogues.

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Expression of Parathyroid Hormone (PTH)-related Peptide (PTHrP) and PTH/PTHrP Receptor in Osteoclast-like Giant Cells

Cited by 15 publications

References 34 publications

PTHrP increases RANKL expression by stromal cells from giant cell tumor of bone

PTHrP increases RANKL expression by stromal cells from giant cell tumor of bone

PTHrP Induces Autocrine/Paracrine Proliferation of Bone Tumor Cells through Inhibition of Apoptosis

Immunohistochemical identification of the PTHR1 parathyroid hormone receptor in normal and neoplastic human tissues

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