Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism1

Tokumoto, Masanori; Tsuruya, Kazuhiko; Fukuda, Keisuke; Kanai, Hidetoshi; Kuroki, Shin-Ichiro; Hirakata, Hideki

doi:10.1046/j.1523-1755.2002.00585.x

Cited by 46 publications

(77 citation statements)

References 34 publications

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“…Figure 5 confirms the reduced VDR levels reported for nodular hyperplasia, 7 which was associated with enhanced TGF-␣ expression and EGFR activation, as measured by increased P-ERK1/2 content; however, high cross-reactivity of the antibody directed to the domain of the C/EBP␤ molecule common for LAP and LIP impedes accurate immunohistochemical analysis of LIP expression in diffuse and nodular areas. Therefore, Western blot analysis was conducted in wholecell extracts from hyperplastic human glands, which accurately measures LAP and LIP levels but fails to discriminate diffuse from nodular areas.…”

Section: Resultssupporting

confidence: 78%

“…[1][2][3][4] The efficacy of 1,25-dihydroxyvitamin D (calcitriol, 1,25D), the hormonal form of vitamin D, to suppress PTH gene expression and parathyroid cell growth has rendered calcitriol or its less calcemic analogs the treatment of choice for secondary hyperparathyroidism (SH) 5 ; however, as kidney disease progresses, parathyroid vitamin D receptor (VDR) levels decrease in parallel with the severity of parathyroid hyperplasia, 6,7 rendering nodular hyperplasia, the most aggressive form of SH, 6 unresponsive to calcitriol (analog) therapy. 7 The lack of appropriate experimental models has impeded earlier characterization of the pathogenesis of the association between the severity of parathyroid hyperplasia and the re-duction of VDR. Primary cultures of parathyroid cells fail to mimic the suppression of growth by either calcitriol or high calcium (Ca) in vivo, as a result of a rapid loss of VDR 8 and Ca-sensing receptor.…”

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confidence: 99%

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EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Arcidiacono

Sato²,

Alvarez-Hernandez³

et al. 2008

Journal of the American Society of Nephrology

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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-␣ 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-␣, the progression of growth, and the reduction of VDR. Increased TGF-␣/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-␤, 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-␤ 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-␣ 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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Section: Resultssupporting

confidence: 78%

mentioning

confidence: 99%

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Arcidiacono

Sato²,

Alvarez-Hernandez³

et al. 2008

Journal of the American Society of Nephrology

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“…The balance between the cellular compartments (nuclear/cytoplasmic) is probably relevant to the regulatory actions of vitamin D. More pronounced cytoplasmic VDR staining could indicate an 'escape' of parathyroid adenoma cells from homeostatic surveillance and growth control, especially if the regulatory mechanisms depended on ligand-activated receptor activity (29). Such alterations in cytoplasmic and nuclear VDR staining have also been reported in other neoplasms (30,31,32).…”

Section: Discussionmentioning

confidence: 81%

Simultaneous expression analysis of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic primary hyperparathyroidism in Asian Indians

Varshney

Bhadada

Saikia

et al. 2013

European Journal of Endocrinology

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Background: To explore underlying molecular mechanisms in the pathogenesis of symptomatic sporadic primary hyperparathyroidism (PHPT). Materials and methods: Forty-one parathyroid adenomas from patients with symptomatic PHPT and ten normal parathyroid glands either from patients with PHPT (nZ3) or from euthyroid patients without PHPT during thyroid surgery (nZ7) were analyzed for vitamin D receptor (VDR), calcium-sensing receptor (CASR), cyclin D1 (CD1), and parathyroid hormone (PTH) expressions. The protein expressions were assessed semiquantitatively by immunohistochemistry, based on percentage of positive cells and staining intensity, and confirmed by quantitative real-time PCR. Results: Immunohistochemistry revealed significant reductions in VDR (both nuclear and cytoplasmic) and CASR expressions and significant increases in CD1 and PTH expressions in adenomatous compared with normal parathyroid tissue. Consistent with immunohistochemistry findings, both VDR and CASR mRNAs were reduced by 0.36-and 0.45-fold change (P!0.001) and CD1 and PTH mRNAs were increased by 9.4-and 17.4-fold change respectively (P!0.001) in adenomatous parathyroid tissue. PTH mRNA correlated with plasma PTH (rZ0.864; P!0.001), but not with adenoma weight, while CD1 mRNA correlated with adenoma weight (rZ0.715; P!0.001). There were no correlations between VDR and CASR mRNA levels and serum Ca, plasma intact PTH, or 25-hydroxyvitamin D levels. In addition, there was no relationship between the decreases in VDR and CASR mRNA expressions and the increases in PTH and CD1 mRNA expressions. Conclusions: The expression of both VDR and CASR are reduced in symptomatic PHPT in Asian Indians. In addition, CD1 expression was greatly increased and correlated with adenoma weight, implying a potential role for CD1 in adenoma growth and differential clinical expression of PHPT.

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“…After treatment washout at the end of 52 weeks, PTH increased to levels higher than baseline in both arms, suggesting that underlying parathyroid disease severity may have worsened over time. Such a progression might be associated with a decrease in expression of the parathyroid calciumsensing and vitamin D receptors (21,22), potentially resulting in treatment resistance; if so, the relatively long treatment duration compared with other trials (1,13) may have made it less likely that either agent could demonstrate effectiveness.…”

Section: Discussionmentioning

confidence: 99%

A Randomized Trial of Cinacalcet versus Vitamin D Analogs as Monotherapy in Secondary Hyperparathyroidism (PARADIGM)

Wetmore

Gurevich²,

Sprague

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Direct comparison of cinacalcet and vitamin D analogs as monotherapies to lower parathyroid hormone (PTH) levels has not been undertaken.Design, setting, participants, & measurements This was a prospective, multicenter, phase 4, randomized, openlabel study that enrolled participants from 2010 to 2012. Adult participants (n=312) on hemodialysis with PTH .450 pg/ml were randomized 1:1 to 12 months of treatment with either cinacalcet (n=155) or vitamin D analogs (n=157) to evaluate the mean percentage change in plasma PTH level (primary end point) and the proportion of participants achieving plasma PTH ,300 pg/ml or a $30% decrease in PTH (secondary end points). A preplanned analysis to determine whether there were important region-by-treatment interactions was also undertaken.Results Baseline mean PTH was 846 pg/ml (n=155) for cinacalcet and 816 pg/ml (n=157) for vitamin D analog therapy. The mean (95% confidence interval) percentage change from baseline in PTH was 212.1% (220.0% to 24.1%) in the cinacalcet arm and 27.0% (214.9% to 0.8%) in the vitamin D analog arm, a difference of 25.0% (215.4% to 5.4%) (P=0.35). Similarly, there was no difference in achievement of secondary efficacy end points between arms (19.4% and 15.3% of participants with PTH#300 pg/ml and 42.6% and 33.8% of participants had a PTH reduction .30% in the cinacalcet and vitamin D analog arms, respectively). A prespecified analysis revealed a large treatment-by-region interaction, with nominally greater response to cinacalcet compared with vitamin D analogs in non-United States participants (US versus non-US participants, P,0.001). Hypocalcemia was more common in the cinacalcet arm, whereas hypercalcemia and hyperphosphatemia occurred more often in the vitamin D analog arm.Conclusions Participants had similar modest reductions in PTH with either cinacalcet or vitamin D analog monotherapy over 52 weeks of treatment, but effects varied by region. Treatments differed with regard to effect on calcium and phosphorus levels.

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Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism1

Abstract: The reduced expression of p21 and p27, in a VDR-dependent manner, is a major pathogenic factor for a nodular parathyroid gland growth.

Cited by 46 publications

References 34 publications

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Simultaneous expression analysis of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic primary hyperparathyroidism in Asian Indians

A Randomized Trial of Cinacalcet versus Vitamin D Analogs as Monotherapy in Secondary Hyperparathyroidism (PARADIGM)

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