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Eduardo Slatopolsky - One of the best experts on this subject based on the ideXlab platform.
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EGFR activation increases Parathyroid hyperplasia and calcitriol resistance in kidney disease.
Journal of the American Society of Nephrology : JASN, 2008Co-Authors: Maria Vittoria Arcidiacono, Masanori Tokumoto, Tetsuhiko Sato, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Jorge B. Cannata-andía, Eduardo SlatopolskyAbstract:Calcitriol, acting through vitamin D receptors (VDR) in the Parathyroid, suppresses Parathyroid hormone synthesis and cell proliferation. In secondary hyperParathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-alpha is required for the development of Parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of Parathyroid TGF-alpha, the progression of growth, and the reduction of VDR. Increased TGF-alpha/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-beta, in human hyperplastic Parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic Parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-beta transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-alpha activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.
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Molecular Basis of Parathyroid hyperplasia
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, 2007Co-Authors: Adriana Dusso, Tetsuhiko Sato, Maria Vittoria Arcidiacono, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Eduardo SlatopolskyAbstract:EARLY ALL PATIENTS with end-stagerenal disease develop secondary hyper-Parathyroidism (SH), a condition characterizedby various degrees of Parathyroid hyperplasia andincreased synthesis and secretion of Parathyroidhormone (PTH). Hypocalcemia, hyperphos-phatemia caused by phosphate retention, and cal-citriol deficiency are the three main causes of SHin chronic kidney disease.' The elevated circulat-ing levels ofPTH cause bone loss, osteitis fibrosa,skeletal abnormalities known as renal osteodys-trophy, and systemic toxicities, including cardio-vascular, endocrine, nervous, irnrnunologic, andcutaneous dysfunctions that markedly increasemorbidity and mortality rates in patients withkidney disease.fNumerous laboratories have contributed to thecurrent understanding of the mechanisms medi-ating the control of PTH synthesis and secretionby changes in serum calcium, phosphorus, andcalcitriollevels in kidney disease. In contrast, thelack of an appropriate Parathyroid cell line andthe rapid dedifferentiation of primary cultures ofhyperplastic Parathyroid cells have impeded anearlier characterization of the pathogenic mech-anisms underlying the induction of Parathyroidcell proliferation by kidney disease, its worseningby either high phosphorus or low dietary calcium
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Pathogenic mechanisms for Parathyroid hyperplasia.
Kidney international. Supplement, 2006Co-Authors: Adriana Dusso, Tetsuhiko Sato, Maria Vittoria Arcidiacono, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Eduardo SlatopolskyAbstract:Parathyroid hyperplasia is the cause of Parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical contributors to the worsening of the hyperplastic Parathyroid growth induced by KD. Reproduction of the features of human KD in the 5/6 nephrectomized rat model has shown that 80% of the mitogenic signals induced by KD in Parathyroid cells that are aggravated by either high phosphate (P) or low calcium (Ca) diets occurred within 5 days after the onset of KD. Enhanced Parathyroid expression of the potent growth promoter transforming growth factor alpha (TGFalpha) and its receptor, the epidermal growth factor receptor (EGFR), was identified as the main cause of Parathyroid hyperplasia in experimental KD. Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGFalpha-activated EGFR, completely prevented high P- and low Ca-induced Parathyroid hyperplasia in early KD, as well as the severe progression of high P-induced Parathyroid growth in established secondary hyperParathyroidism, the latter characterized by marked TGFalpha and EGFR overexpression in the Parathyroid glands. More importantly, the suppression of signals downstream from TGFalpha binding to EGFR with EGFR-TKI treatment also revealed that TGFalpha self-upregulation in the Parathyroid glands is the main determinant of the severity of the hyperplastic growth, and that enhanced TGFalpha activation of EGFR mediates the reduction in Parathyroid vitamin D receptor levels thereby causing resistance to both the antiproliferative and Parathyroid hormone-suppressive properties of calcitriol therapy.
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A critical role for enhanced TGF-α and EGFR expression in the initiation of Parathyroid hyperplasia in experimental kidney disease
American journal of physiology. Renal physiology, 2005Co-Authors: Mario Cozzolino, Tetsuhiko Sato, Jing Yang, Eduardo Slatopolsky, Diego Brancaccio, Ignacio Gonzalez Suarez, Adriana DussoAbstract:The Parathyroid hyperplasia secondary to kidney disease is associated with enhanced expression of the growth promoter transforming growth factor-α (TGF-α). TGF-α stimulates growth through activatio...
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Pathogenesis of Parathyroid hyperplasia in renal failure.
Journal of nephrology, 2005Co-Authors: Mario Cozzolino, Eduardo Slatopolsky, Diego Brancaccio, Maurizio Gallieni, Andrea Galassi, Adriana DussoAbstract:In chronic kidney disease, secondary hyperParathyroidism (HPTH) is characterized by Parathyroid hyperplasia and enhanced synthesis and secretion of Parathyroid hormone (PTH). Elevated PTH levels cause renal osteodistrophy and cardiovascular complications, with significantly increased morbidity and mortality in renal failure. The three main direct causes of renal HPTH are hypocalcemia, hyperphosphatemia and vitamin D deficiency. A link between the mechanisms controlling proliferation and hormonal production also exists in normal Parathyroid cells which respond to the stimulus of chronic hypocalcemia, not only by an increase in PTH release but also with a consequent Parathyroid cell proliferation. The mechanisms responsible for this link, however, remain poorly understood. In this review, we analyze the current understanding concerning the new insights into the molecular mechanisms of Parathyroid hyperplasia and PTH secretion in renal failure regulated by calcium, phosphate and vitamin D.
Adriana Dusso - One of the best experts on this subject based on the ideXlab platform.
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Parathyroid-specific epidermal growth factor-receptor inactivation prevents uremia-induced Parathyroid hyperplasia in mice
Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2014Co-Authors: Maria Vittoria Arcidiacono, Jing Yang, Elvira Fernández, Adriana DussoAbstract:Background In chronic kidney disease (CKD), Parathyroid hyperplasia contributes to high serum Parathyroid hormone (PTH) and also to an impaired suppression of secondary hyperParathyroidism by calcium, vitamin D and fibroblast growth factor 23 (FGF23). In rats, systemic inhibition of epidermal growth factor receptor (EGFR) activation markedly attenuated uremia-induced Parathyroid hyperplasia and vitamin D receptor (VDR) loss, hence restoring the response to vitamin D. Therefore, we propose that Parathyroid-specific EGFR inactivation should prevent CKD-induced Parathyroid hyperplasia.
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The induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and Parathyroid hyperplasia in kidney disease
Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2014Co-Authors: Maria Vittoria Arcidiacono, Jing Yang, Elvira Fernández, Adriana DussoAbstract:Abstract BACKGROUND: In secondary hyperParathyroidism (SHPT), enhanced Parathyroid levels of transforming growth factor-α (TGFα) increase EGF receptor (EGFR) activation causing Parathyroid hyperplasia, high Parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress Parathyroid hyperplasia because ADAM17 is required to release mature TGFα, the most potent EGFR-activating ligand. METHODS: Computer analysis of the ADAM17 promoter identified TGFα and C/EBPβ as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGFα/EGFR-driven growth and Parathyroid gland (PTG) enlargement were assessed in promoter-reporter assays in A431 cells and corroborated in rat and human SHPT, using erlotinib as anti-EGFR therapy to suppress TGFα signals, active vitamin D to induce C/EBPβ or the combination. RESULTS: While TGFα induced ADAM17-promoter activity by 2.2-fold exacerbating TGFα/EGFR-driven growth, ectopic C/EBPβ expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, Parathyroid ADAM17 levels correlated directly with TGFα and inversely with C/EBPβ. Furthermore, combined erlotinib + calcitriol treatment suppressed TGFα/EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBPβ to inhibit ADAM17-promoter activity, mRNA and protein. Importantly, in rat SHPT, the correction of vitamin D deficiency effectively reversed the resistance to paricalcitol induction of C/EBPβ to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%. CONCLUSION: In SHPT, correction of vitamin D and calcitriol deficiency induces Parathyroid C/EBPβ to efficaciously attenuate the severe ADAM17/TGFα synergy, which drives PTG enlargement and high PTH.
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Molecular Basis of Parathyroid hyperplasia
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, 2007Co-Authors: Adriana Dusso, Tetsuhiko Sato, Maria Vittoria Arcidiacono, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Eduardo SlatopolskyAbstract:EARLY ALL PATIENTS with end-stagerenal disease develop secondary hyper-Parathyroidism (SH), a condition characterizedby various degrees of Parathyroid hyperplasia andincreased synthesis and secretion of Parathyroidhormone (PTH). Hypocalcemia, hyperphos-phatemia caused by phosphate retention, and cal-citriol deficiency are the three main causes of SHin chronic kidney disease.' The elevated circulat-ing levels ofPTH cause bone loss, osteitis fibrosa,skeletal abnormalities known as renal osteodys-trophy, and systemic toxicities, including cardio-vascular, endocrine, nervous, irnrnunologic, andcutaneous dysfunctions that markedly increasemorbidity and mortality rates in patients withkidney disease.fNumerous laboratories have contributed to thecurrent understanding of the mechanisms medi-ating the control of PTH synthesis and secretionby changes in serum calcium, phosphorus, andcalcitriollevels in kidney disease. In contrast, thelack of an appropriate Parathyroid cell line andthe rapid dedifferentiation of primary cultures ofhyperplastic Parathyroid cells have impeded anearlier characterization of the pathogenic mech-anisms underlying the induction of Parathyroidcell proliferation by kidney disease, its worseningby either high phosphorus or low dietary calcium
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Pathogenic mechanisms for Parathyroid hyperplasia.
Kidney international. Supplement, 2006Co-Authors: Adriana Dusso, Tetsuhiko Sato, Maria Vittoria Arcidiacono, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Eduardo SlatopolskyAbstract:Parathyroid hyperplasia is the cause of Parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical contributors to the worsening of the hyperplastic Parathyroid growth induced by KD. Reproduction of the features of human KD in the 5/6 nephrectomized rat model has shown that 80% of the mitogenic signals induced by KD in Parathyroid cells that are aggravated by either high phosphate (P) or low calcium (Ca) diets occurred within 5 days after the onset of KD. Enhanced Parathyroid expression of the potent growth promoter transforming growth factor alpha (TGFalpha) and its receptor, the epidermal growth factor receptor (EGFR), was identified as the main cause of Parathyroid hyperplasia in experimental KD. Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGFalpha-activated EGFR, completely prevented high P- and low Ca-induced Parathyroid hyperplasia in early KD, as well as the severe progression of high P-induced Parathyroid growth in established secondary hyperParathyroidism, the latter characterized by marked TGFalpha and EGFR overexpression in the Parathyroid glands. More importantly, the suppression of signals downstream from TGFalpha binding to EGFR with EGFR-TKI treatment also revealed that TGFalpha self-upregulation in the Parathyroid glands is the main determinant of the severity of the hyperplastic growth, and that enhanced TGFalpha activation of EGFR mediates the reduction in Parathyroid vitamin D receptor levels thereby causing resistance to both the antiproliferative and Parathyroid hormone-suppressive properties of calcitriol therapy.
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A critical role for enhanced TGF-α and EGFR expression in the initiation of Parathyroid hyperplasia in experimental kidney disease
American journal of physiology. Renal physiology, 2005Co-Authors: Mario Cozzolino, Tetsuhiko Sato, Jing Yang, Eduardo Slatopolsky, Diego Brancaccio, Ignacio Gonzalez Suarez, Adriana DussoAbstract:The Parathyroid hyperplasia secondary to kidney disease is associated with enhanced expression of the growth promoter transforming growth factor-α (TGF-α). TGF-α stimulates growth through activatio...
Yoshihiro Tominaga - One of the best experts on this subject based on the ideXlab platform.
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EGFR activation increases Parathyroid hyperplasia and calcitriol resistance in kidney disease.
Journal of the American Society of Nephrology : JASN, 2008Co-Authors: Maria Vittoria Arcidiacono, Masanori Tokumoto, Tetsuhiko Sato, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Jorge B. Cannata-andía, Eduardo SlatopolskyAbstract:Calcitriol, acting through vitamin D receptors (VDR) in the Parathyroid, suppresses Parathyroid hormone synthesis and cell proliferation. In secondary hyperParathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-alpha is required for the development of Parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of Parathyroid TGF-alpha, the progression of growth, and the reduction of VDR. Increased TGF-alpha/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-beta, in human hyperplastic Parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic Parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-beta transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-alpha activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.
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Molecular Basis of Parathyroid hyperplasia
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, 2007Co-Authors: Adriana Dusso, Tetsuhiko Sato, Maria Vittoria Arcidiacono, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Eduardo SlatopolskyAbstract:EARLY ALL PATIENTS with end-stagerenal disease develop secondary hyper-Parathyroidism (SH), a condition characterizedby various degrees of Parathyroid hyperplasia andincreased synthesis and secretion of Parathyroidhormone (PTH). Hypocalcemia, hyperphos-phatemia caused by phosphate retention, and cal-citriol deficiency are the three main causes of SHin chronic kidney disease.' The elevated circulat-ing levels ofPTH cause bone loss, osteitis fibrosa,skeletal abnormalities known as renal osteodys-trophy, and systemic toxicities, including cardio-vascular, endocrine, nervous, irnrnunologic, andcutaneous dysfunctions that markedly increasemorbidity and mortality rates in patients withkidney disease.fNumerous laboratories have contributed to thecurrent understanding of the mechanisms medi-ating the control of PTH synthesis and secretionby changes in serum calcium, phosphorus, andcalcitriollevels in kidney disease. In contrast, thelack of an appropriate Parathyroid cell line andthe rapid dedifferentiation of primary cultures ofhyperplastic Parathyroid cells have impeded anearlier characterization of the pathogenic mech-anisms underlying the induction of Parathyroidcell proliferation by kidney disease, its worseningby either high phosphorus or low dietary calcium
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Pathogenic mechanisms for Parathyroid hyperplasia.
Kidney international. Supplement, 2006Co-Authors: Adriana Dusso, Tetsuhiko Sato, Maria Vittoria Arcidiacono, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Eduardo SlatopolskyAbstract:Parathyroid hyperplasia is the cause of Parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical contributors to the worsening of the hyperplastic Parathyroid growth induced by KD. Reproduction of the features of human KD in the 5/6 nephrectomized rat model has shown that 80% of the mitogenic signals induced by KD in Parathyroid cells that are aggravated by either high phosphate (P) or low calcium (Ca) diets occurred within 5 days after the onset of KD. Enhanced Parathyroid expression of the potent growth promoter transforming growth factor alpha (TGFalpha) and its receptor, the epidermal growth factor receptor (EGFR), was identified as the main cause of Parathyroid hyperplasia in experimental KD. Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGFalpha-activated EGFR, completely prevented high P- and low Ca-induced Parathyroid hyperplasia in early KD, as well as the severe progression of high P-induced Parathyroid growth in established secondary hyperParathyroidism, the latter characterized by marked TGFalpha and EGFR overexpression in the Parathyroid glands. More importantly, the suppression of signals downstream from TGFalpha binding to EGFR with EGFR-TKI treatment also revealed that TGFalpha self-upregulation in the Parathyroid glands is the main determinant of the severity of the hyperplastic growth, and that enhanced TGFalpha activation of EGFR mediates the reduction in Parathyroid vitamin D receptor levels thereby causing resistance to both the antiproliferative and Parathyroid hormone-suppressive properties of calcitriol therapy.
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expression of prad1 cyclin d1 retinoblastoma gene products and ki67 in Parathyroid hyperplasia caused by chronic renal failure versus primary adenoma
Kidney International, 1999Co-Authors: Yoshihiro Tominaga, Yuji Tanaka, Masahiro Numano, Toyonori Tsuzuki, K Uchida, T Haba, Satoki Otsuka, Toshihiro Ichimori, Kazuhiro Yamada, Hiroshi TakagiAbstract:Expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in Parathyroid hyperplasia caused by chronic renal failure versus primary adenoma. Background In primary hyperParathyroidism, certain genetic abnormalities responsible for Parathyroid tumorigenesis are proposed, and it has been reported that the overexpression of PRAD1/cyclin D1 induced by a DNA rearrangement of the Parathyroid hormone (PTH) gene is one of the genetic disorders in a number of primary Parathyroid adenomas. However, in secondary hyperParathyroidism caused by uremia, the mechanism of monoclonal proliferation in nodular Parathyroid hyperplasia is not well understood. To elucidate the mechanism, we examined the expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in primary adenoma and secondary hyperplasia. Methods In adenomas ( N = 15) and associated glands ( N = 7) with normal histology obtained from patients with primary hyperParathyroidism and in diffuse ( N = 14), multinodular ( N = 58), and single nodular ( N = 28) glands from patients who underwent Parathyroidectomy for renal hyperParathyroidism, the expression of these cell cycle regulators was evaluated by immunohistochemical technique. A labeling index was used to define the proportion of cells with positive nuclear staining by each antibody. Results In 6 out of 15 (40%) primary adenomas, PRAD1/cyclin D1 was overexpressed (a labeling index of more than 500), possibly because of the PTH gene rearrangement, but not in secondary hyperplasia, including single nodular glands. Compared with diffuse hyperplasia, nodular hyperplasia showed a significantly higher expression of PRAD1/cyclin D1 ( P P P Conclusions These results suggest that in secondary hyperplasia caused by uremia, at least remarkable overexpression of PRAD1/cyclin D1 induced by PTH gene rearrangement may be not the major genetic abnormality responsible for tumorigenesis. Heterogenous genetic changes seem to contribute to monoclonal proliferation of Parathyroid cells induced by the expression of PRAD1/cyclin D1 or by some other mechanism independent of the amplification of the proto-oncogene.
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Hyperphosphatemia Accelerates Parathyroid Cell Proliferation and Parathyroid Hormone Secretion in Severe Secondary Parathyroid hyperplasia.
Endocrine journal, 1999Co-Authors: Yasuyuki Hayakawa, Yuji Tanaka, Yoshihiro Tominaga, Hiroomi Funahashi, Tsuneo Imai, Nami Matsuura, Mikinao Oiwa, Toyone Kikumori, Takahiro Mase, Akimasa NakaoAbstract:We studied the role of phosphorus retention in Parathyroid cell proliferation and Parathyroid hormone (PTH) oversecretion in severe secondary Parathyroid hyperplasia. Mice transplanted with human Parathyroid tissue from a patient who had undergone Parathyroidectomy for severe secondary hyperParathyroidism were divided into four groups; each group was given a diet with a different phosphorus content (0.4, 0.7, 1.0, and 1.2%) to alter serum phosphorus concentrations. Histologic examinations of grafts by hematoxylin-eosin or by bromodeoxyuridine (BrdU) immunohistochemical staining were performed to assess Parathyroid cell proliferation. Changes in serum phosphorus concentrations unidirectionally affected PTH secretion from the graft, because human PTH did not cross-react with mouse PTH. Serum phosphorus concentrations of 1.0P and 1.2P groups were significantly higher than those of 0.4P and 0.7P groups (p
Tetsuhiko Sato - One of the best experts on this subject based on the ideXlab platform.
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EGFR activation increases Parathyroid hyperplasia and calcitriol resistance in kidney disease.
Journal of the American Society of Nephrology : JASN, 2008Co-Authors: Maria Vittoria Arcidiacono, Masanori Tokumoto, Tetsuhiko Sato, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Jorge B. Cannata-andía, Eduardo SlatopolskyAbstract:Calcitriol, acting through vitamin D receptors (VDR) in the Parathyroid, suppresses Parathyroid hormone synthesis and cell proliferation. In secondary hyperParathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-alpha is required for the development of Parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of Parathyroid TGF-alpha, the progression of growth, and the reduction of VDR. Increased TGF-alpha/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-beta, in human hyperplastic Parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic Parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-beta transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-alpha activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.
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Molecular Basis of Parathyroid hyperplasia
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, 2007Co-Authors: Adriana Dusso, Tetsuhiko Sato, Maria Vittoria Arcidiacono, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Eduardo SlatopolskyAbstract:EARLY ALL PATIENTS with end-stagerenal disease develop secondary hyper-Parathyroidism (SH), a condition characterizedby various degrees of Parathyroid hyperplasia andincreased synthesis and secretion of Parathyroidhormone (PTH). Hypocalcemia, hyperphos-phatemia caused by phosphate retention, and cal-citriol deficiency are the three main causes of SHin chronic kidney disease.' The elevated circulat-ing levels ofPTH cause bone loss, osteitis fibrosa,skeletal abnormalities known as renal osteodys-trophy, and systemic toxicities, including cardio-vascular, endocrine, nervous, irnrnunologic, andcutaneous dysfunctions that markedly increasemorbidity and mortality rates in patients withkidney disease.fNumerous laboratories have contributed to thecurrent understanding of the mechanisms medi-ating the control of PTH synthesis and secretionby changes in serum calcium, phosphorus, andcalcitriollevels in kidney disease. In contrast, thelack of an appropriate Parathyroid cell line andthe rapid dedifferentiation of primary cultures ofhyperplastic Parathyroid cells have impeded anearlier characterization of the pathogenic mech-anisms underlying the induction of Parathyroidcell proliferation by kidney disease, its worseningby either high phosphorus or low dietary calcium
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Pathogenic mechanisms for Parathyroid hyperplasia.
Kidney international. Supplement, 2006Co-Authors: Adriana Dusso, Tetsuhiko Sato, Maria Vittoria Arcidiacono, Daniel Álvarez-hernández, Jing Yang, Ignacio Gonzalez-suarez, Yoshihiro Tominaga, Eduardo SlatopolskyAbstract:Parathyroid hyperplasia is the cause of Parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical contributors to the worsening of the hyperplastic Parathyroid growth induced by KD. Reproduction of the features of human KD in the 5/6 nephrectomized rat model has shown that 80% of the mitogenic signals induced by KD in Parathyroid cells that are aggravated by either high phosphate (P) or low calcium (Ca) diets occurred within 5 days after the onset of KD. Enhanced Parathyroid expression of the potent growth promoter transforming growth factor alpha (TGFalpha) and its receptor, the epidermal growth factor receptor (EGFR), was identified as the main cause of Parathyroid hyperplasia in experimental KD. Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGFalpha-activated EGFR, completely prevented high P- and low Ca-induced Parathyroid hyperplasia in early KD, as well as the severe progression of high P-induced Parathyroid growth in established secondary hyperParathyroidism, the latter characterized by marked TGFalpha and EGFR overexpression in the Parathyroid glands. More importantly, the suppression of signals downstream from TGFalpha binding to EGFR with EGFR-TKI treatment also revealed that TGFalpha self-upregulation in the Parathyroid glands is the main determinant of the severity of the hyperplastic growth, and that enhanced TGFalpha activation of EGFR mediates the reduction in Parathyroid vitamin D receptor levels thereby causing resistance to both the antiproliferative and Parathyroid hormone-suppressive properties of calcitriol therapy.
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A critical role for enhanced TGF-α and EGFR expression in the initiation of Parathyroid hyperplasia in experimental kidney disease
American journal of physiology. Renal physiology, 2005Co-Authors: Mario Cozzolino, Tetsuhiko Sato, Jing Yang, Eduardo Slatopolsky, Diego Brancaccio, Ignacio Gonzalez Suarez, Adriana DussoAbstract:The Parathyroid hyperplasia secondary to kidney disease is associated with enhanced expression of the growth promoter transforming growth factor-α (TGF-α). TGF-α stimulates growth through activatio...
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1,25-Dihydroxyvitamin D downregulation of TGFα/EGFR expression and growth signaling: a mechanism for the antiproliferative actions of the sterol in Parathyroid hyperplasia of renal failure
The Journal of Steroid Biochemistry and Molecular Biology, 2004Co-Authors: Adriana Dusso, Tetsuhiko Sato, Mario Cozzolino, Eduardo SlatopolskyAbstract:Elevated serum levels of Parathyroid hormone (PTH) contribute to the increased morbidity and mortality in renal failure patients. Parathyroid gland hyperplasia is a major cause of high serum PTH. The present studies used the rat model of renal failure to address the mechanisms underlying uremia-induced Parathyroid hyperplasia and the antiproliferative properties of vitamin D therapy (1,25-dihydroxyvitamin D (1,25(OH)(2)D(3)) or its less calcemic analogs). Enhanced TGFalpha/EGFR co-expression is the major mitogenic signal in uremic Parathyroid glands. At early stages of renal failure, vitamin D therapy efficiently counteracts uremia- and high phosphorus-induced hyperplasia by inhibiting the increases in Parathyroid-TGFalpha/EGFR co-expression. In established hyperParathyroidism, characterized by highly enhanced-TGFalpha/EGFR co-expression, vitamin D therapy arrests growth by suppressing EGFR-growth signals from the plasma membrane and nuclear EGFR actions as a transactivator of the cyclin D1 gene, an important contributor to Parathyroid hyperplasia in humans. In advanced renal failure, reduced-Parathyroid vitamin D receptor levels limits the antiproliferative efficacy of vitamin D therapy. However, non-antiproliferative doses of 1,25-dihydroxyvitamin D enhance the anti-EGFR actions of EGFR-tyrosine kinase inhibitors (TKI). In fact, combined 1,25-dihydroxyvitamin D/TKI therapy inhibits Parathyroid hyperplasia more efficiently than phosphorus restriction, the most powerful promoter of Parathyroid growth arrest available at present.
Hiroshi Takagi - One of the best experts on this subject based on the ideXlab platform.
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expression of prad1 cyclin d1 retinoblastoma gene products and ki67 in Parathyroid hyperplasia caused by chronic renal failure versus primary adenoma
Kidney International, 1999Co-Authors: Yoshihiro Tominaga, Yuji Tanaka, Masahiro Numano, Toyonori Tsuzuki, K Uchida, T Haba, Satoki Otsuka, Toshihiro Ichimori, Kazuhiro Yamada, Hiroshi TakagiAbstract:Expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in Parathyroid hyperplasia caused by chronic renal failure versus primary adenoma. Background In primary hyperParathyroidism, certain genetic abnormalities responsible for Parathyroid tumorigenesis are proposed, and it has been reported that the overexpression of PRAD1/cyclin D1 induced by a DNA rearrangement of the Parathyroid hormone (PTH) gene is one of the genetic disorders in a number of primary Parathyroid adenomas. However, in secondary hyperParathyroidism caused by uremia, the mechanism of monoclonal proliferation in nodular Parathyroid hyperplasia is not well understood. To elucidate the mechanism, we examined the expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in primary adenoma and secondary hyperplasia. Methods In adenomas ( N = 15) and associated glands ( N = 7) with normal histology obtained from patients with primary hyperParathyroidism and in diffuse ( N = 14), multinodular ( N = 58), and single nodular ( N = 28) glands from patients who underwent Parathyroidectomy for renal hyperParathyroidism, the expression of these cell cycle regulators was evaluated by immunohistochemical technique. A labeling index was used to define the proportion of cells with positive nuclear staining by each antibody. Results In 6 out of 15 (40%) primary adenomas, PRAD1/cyclin D1 was overexpressed (a labeling index of more than 500), possibly because of the PTH gene rearrangement, but not in secondary hyperplasia, including single nodular glands. Compared with diffuse hyperplasia, nodular hyperplasia showed a significantly higher expression of PRAD1/cyclin D1 ( P P P Conclusions These results suggest that in secondary hyperplasia caused by uremia, at least remarkable overexpression of PRAD1/cyclin D1 induced by PTH gene rearrangement may be not the major genetic abnormality responsible for tumorigenesis. Heterogenous genetic changes seem to contribute to monoclonal proliferation of Parathyroid cells induced by the expression of PRAD1/cyclin D1 or by some other mechanism independent of the amplification of the proto-oncogene.
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Expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in Parathyroid hyperplasia caused by chronic renal failure versus primary adenoma
Kidney international, 1999Co-Authors: Yoshihiro Tominaga, Yuji Tanaka, Toshihito Haba, Kazuharu Uchida, Masahiro Numano, Toyonori Tsuzuki, Satoki Otsuka, Toshihiro Ichimori, Kazuhiro Yamada, Hiroshi TakagiAbstract:Expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in Parathyroid hyperplasia caused by chronic renal failure versus primary adenoma. Background In primary hyperParathyroidism, certain genetic abnormalities responsible for Parathyroid tumorigenesis are proposed, and it has been reported that the overexpression of PRAD1/cyclin D1 induced by a DNA rearrangement of the Parathyroid hormone (PTH) gene is one of the genetic disorders in a number of primary Parathyroid adenomas. However, in secondary hyperParathyroidism caused by uremia, the mechanism of monoclonal proliferation in nodular Parathyroid hyperplasia is not well understood. To elucidate the mechanism, we examined the expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in primary adenoma and secondary hyperplasia. Methods In adenomas ( N = 15) and associated glands ( N = 7) with normal histology obtained from patients with primary hyperParathyroidism and in diffuse ( N = 14), multinodular ( N = 58), and single nodular ( N = 28) glands from patients who underwent Parathyroidectomy for renal hyperParathyroidism, the expression of these cell cycle regulators was evaluated by immunohistochemical technique. A labeling index was used to define the proportion of cells with positive nuclear staining by each antibody. Results In 6 out of 15 (40%) primary adenomas, PRAD1/cyclin D1 was overexpressed (a labeling index of more than 500), possibly because of the PTH gene rearrangement, but not in secondary hyperplasia, including single nodular glands. Compared with diffuse hyperplasia, nodular hyperplasia showed a significantly higher expression of PRAD1/cyclin D1 ( P P P Conclusions These results suggest that in secondary hyperplasia caused by uremia, at least remarkable overexpression of PRAD1/cyclin D1 induced by PTH gene rearrangement may be not the major genetic abnormality responsible for tumorigenesis. Heterogenous genetic changes seem to contribute to monoclonal proliferation of Parathyroid cells induced by the expression of PRAD1/cyclin D1 or by some other mechanism independent of the amplification of the proto-oncogene.
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Clonal analysis of nodular Parathyroid hyperplasia in renal hyperParathyroidism
World journal of surgery, 1996Co-Authors: Yoshihiro Tominaga, Yuji Tanaka, Setsuko Kohara, Y Namii, Takaharu Nagasaka, Toshihito Haba, Kazuharu Uchida, Masahiro Numano, Hiroshi TakagiAbstract:Although it is well known that chronic renal failure induces Parathyroid hyperplasia, the pathogenesis and development of this Parathyroid lesion in this disease are poorly understood. Histopathologically, there is progression from diffuse to nodular hyperplasia, and each nodule consists of a single cell type with aggressive proliferative potential. Pathophysiologic and clinical investigations have suggested that neoplastic tumors may emerge from nodular hyperplasia. In this study the clonality of Parathyroid tissue in nodular and diffuse hyperplasia in renal hyperParathyroidism was analyzed by a method based on restriction fragment length polymorphism of the X chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation. DNA of peripheral lymphocytes was screened in 43 women undergoing Parathyroidectomy for advanced renal hyperParathyroidism, and 10 of these patients appeared to be heterozygous. Fourteen specimens from these patients were available for clonal analysis. The analysis showed that all four specimens of diffuse hyperplasia were polyclonal, whereas all seven specimens from nodules in nodular hyperplasia and all three samples representing Parathyroid tissue removed from forearm because of graft-dependent recurrence were revealed to be monoclonal. It is likely that the clonal origin of each nodule is independent. These results suggest that in renal hyperParathyroidism Parathyroid glands initially grow diffusely and polyclonally, and then the cells in the nodules are later transformed monoclonally and proliferate aggressively. From the present study it can be concluded that nodular hyperplasia represents monoclonal Parathyroid neoplasia, which might explain why patients with nodular hyperplasia in renal hyperParathyroidism are refractory to medical treatment, requiring Parathyroidectomy. To prevent recurrences, nodular hyperplastic tissue should not be left at surgery.
