Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice

Imanishi, Yasuo; Hosokawa, Yoshitaka; Yoshimoto, Katsuhiko; Schipani, Ernestina; Mallya, Sanjay M.; Παπανικολάου, Αλέξανδρος; Kifor, Olga; Tokura, Takehiko; Sablosky, Marilyn; Ledgard, Felicia; Gronowicz, Gloria; Wang, Yichen; Schmidt, Emmett V.; Hall, Charles B.; Brown, Edward M.; Bronson, Roderick; Arnold, Andrew

doi:10.1172/jci10523

Cited by 216 publications

(158 citation statements)

References 41 publications

(39 reference statements)

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“…Despite this evidence of persistently augmented bone matrix synthesis, osteoid volume was reduced, and the MAR and BMD were improved in the presence of ambient hypercalcemia, even in the face of hypophosphatemia. This constellation of hypercalcemia and elevated PTH, without significant osteomalacia, that was observed in the double mutants on a rescue diet is also observed in murine models of primary hyperparathyroidism (28) and in human hyperparathyroidism (29) despite hypophosphatemia. Thus our present studies demonstrating improved mineralization in hypercalcemic Casr À/À 1a(OH)ase À/À mice also support a direct role for calcium in bone mineralization.…”

Section: Discussionsupporting

confidence: 59%

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

Richard

Huo

Samadfam

et al. 2010

Journal of Bone and Mineral Research

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We examined parathyroid and skeletal function in 3-month-old mice expressing the null mutation for 25-hydroxyvitamin D-1a-hydroxylase [1a(OH)ase À/À ] and in mice expressing the null mutation for both the 1a(OH)ase and the calcium-sensing receptor [Casr À/À 1a(OH)ase À/À ] genes. On a normal diet, all mice were hypocalcemic, with markedly increased parathyroid hormone (PTH), increased trabecular bone volume, increased osteoblast activity, poorly mineralized bone, enlarged and distorted cartilaginous growth plates, and marked growth retardation, especially in the compound mutants. Osteoclast numbers were reduced in the Casr À/À 1a(OH)ase À/À mice. On a high-lactose, high-calcium, high-phosphorus ''rescue'' diet, serum calcium and PTH were normal in the 1a(OH)ase À/À mice but increased in the Casr À/À 1a(OH)ase À/À mice with reduced serum phosphorus. Growth plate architecture and mineralization were improved in both mutants, but linear growth of the double mutants remained abnormal. Mineralization of bone improved in all mice, but osteoblast activity and trabecular bone volume remained elevated in the Casr À/À 1a(OH)ase À/À mice. These studies support a role for calcium-stimulated maturation of the cartilaginous growth plate and mineralization of the growth plate and bone and calcium-stimulated CaSR-mediated effects on bone resorption. PTH-mediated bone resorption may require calcium-stimulated CaSR-mediated enhancement of osteoclastic activity. ß

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Section: Discussionsupporting

confidence: 59%

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

Richard

Huo

Samadfam

et al. 2010

Journal of Bone and Mineral Research

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“…As such, it is not clear whether the proliferation of the parathyroid cells is the consequence of a downregulated expression of the CaR or whether there are decreased levels of the CaR because the parathyroid cells are proliferating rapidly and proliferating cells lack a well-formed CaR. Recent reports indicate that the proliferation of the PG may precede the downregulation of the CaR (22,23). In this study, we did not examine whether the parathyroid cell proliferation was inhibited after reversal of uremia.…”

Section: Discussionmentioning

confidence: 87%

Persistent Downregulation of Calcium-Sensing Receptor mRNA in Rat Parathyroids when Severe Secondary Hyperparathyroidism Is Reversed by an Isogenic Kidney Transplantation

Lewin¹,

Garfia

Recio

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Experimental severe secondary hyperparathyroidism (HPT) is reversed within 1 wk after reversal of uremia by an isogenic kidney transplantation (KT) in the uremic rats. Abnormal parathyroid hormone (PTH) secretion in uremia is related to downregulation of CaR and vitamin D receptor (VDR) in the parathyroid glands (PG). The aim of this investigation was to examine the expression of CaR and VDR genes after reversal of uremia and HPT in KT rats. 5/6 nephrectomized rats were kept on a normal or high-phosphorus (hP) diet for 8 wk to induce severe HPT (n ϭ 8 in each group). In another group of seven uremic hP rats, uremia was reversed by an isogenic KT and PG were harvested within 1 wk posttransplant. Plasma urea, creatinine, total calcium, phosphorus, and PTH levels were measured. Parathyroid CaR and VDR mRNA were measured by quantitative PCR. Uremic hP rats had significantly elevated levels of creatinine, urea, and phosphorus (P Ͻ 0.001) and developed significant hypocalcemia (plasma calcium 1.83 Ϯ 0.2 mmol/L; P Ͻ 0.001) compared with normal control rats. After KT, the levels were normalized from day 3 to 7: creatinine from 0.117 Ϯ 0.016 to 0.050 Ϯ 0.002 mmol/L; urea from 23 Ϯ 4 to 7 Ϯ 0.3 mmol/L; phosphorus from 3.9 Ϯ 0.6 to 1.5 Ϯ 0.06 mmol/L; calcium from 1.8 Ϯ 0.2 to 2.5 Ϯ 0.02 mmol/L. Plasma PTH levels fell from 849 Ϯ 224 to a normal level of 38 Ϯ 9 pg/ml (P Ͻ 0.01). In uremic rats on a standard diet, CaR mRNA was similar to that of normal control rats, whereas VDR mRNA was significantly decreased. In uremic rats kept on hP diet, CaR mRNA was significantly decreased to 26 Ϯ 7% of control rats (P ϭ 0.01) and VDR mRNA reduced to 36 Ϯ 11% (P Ͻ 0.01). In KT, previously hP uremic rats, both CaR mRNA and VDR mRNA remained severely reduced (CaR, 39 Ϯ 7%; VDR, 9 Ϯ 3%; P Ͻ 0.01) compared with normal rats. In conclusion, circulating plasma PTH levels normalized rapidly after KT, despite persisting downregulation of CaR and VDR gene expression. This indicates that upregulation of CaR mRNA and VDR mRNA is not necessary to induce the rapid normalization of PTH secretion from hyperplastic parathyroid glands.In chronic uremia, the parathyroid gland (PG) function is abnormal, resulting in an increase in parathyroid hormone (PTH) biosynthesis and secretion and parathyroid cell hyperplasia (1,2,3). The molecular basis for the abnormal PTH secretion still remains partly obscure. It presumably involves dysfunction of the mechanism by which the parathyroid cells sense changes in plasma calcium (4). PG from patients with severe secondary or tertiary hyperparathyroidism (HPT) have an elevated set-point for Ca ϩϩ in vitro (5). A substantial reduction in the expression of the Ca ϩϩ -sensing receptor (CaR) protein and mRNA has been demonstrated in hyperplastic parathyroid glands from uremic patients (6,7). 1,25(OH) 2 D 3 dramatically decreases PTH gene transcription (8), and it has been proposed that this sterol also influences the sensitivity of the parathyroid cells to Ca ϩϩ (9). Changes in the vitamin D receptor (VDR) concent...

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“…Frolik et al (2003) have shown that once-daily injection of hPTH1-34 (80 µg/kg per day) increased bone mass in rats, whereas repeated hourly injections over 6 h (6 (13·3 µg/kg per h)) at a total dose of 80 µg/kg per day PTH decreased bone mass. Imanishi et al (2001) have created transgenic mice with parathyroid-targeted overexpression of cyclin D1 and demonstrated that these mice exhibited an abnormal relationship between serum calcium and PTH response, similar to that seen in human primary hyperparathyroidism caused by sporadic parathyroid gland hyperplasia (Arnold et al 2002). Although this transgenic mouse model is an attractive model of hyperparathyroidism, it would also be desirable to develop a model of hyperparathyroidism in wild-type mice that can be produced by simple manipulation or treatment without disruption of genetic structures, allowing studies of the catabolic and anabolic effects of PTH in transgenic mice with various genetic manipulations.…”

Section: Introductionmentioning

confidence: 98%

Short-term continuous infusion of human parathyroid hormone 1–34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice

Iida-Klein

Lu²,

Kapadia³

et al. 2005

Journal of Endocrinology

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Parathyroid hormone (PTH) stimulates bone resorption as well as bone formation in vivo and in organ culture. The catabolic actions of PTH have been recognized in patients with hyperparathyroidism, or with acute infusion of the N-terminal 1-34 fragment of human PTH (hPTH1-34). Whereas the anabolic actions of daily injection with PTH have been well studied in both humans and mice, the catabolic actions of PTH on murine bone remain to be defined. To do this we sought to create a model with short-term, sustained hyperparathyroidism using osmotic infusion pumps. We treated 10-week-old female C57BL/J6 mice with continuous infusion of hPTH1-34 (8·1 pmol/0·25 µl per h, equivalent to 40 µg/kg per day) or vehicle for 2 weeks, using Alzet osmotic pumps. Bone mineral density (BMD), serum total calcium, hPTH1-34, mouse intact PTH (mPTH1-84), osteocalcin and mouse tartrate-resistant acid phosphatase (mTRAP) activity, and microarchitectural variables of the distal femur were measured. Separately, we compared the effects of intermittent daily injection of hPTH1-34 (40 µg/kg per day) with continuous infusion of hPTH1-34 on BMD and bone markers. Exogenous hPTH1-34 was detected only in the PTH-infused mice. Both intermittent and continuous treatment with hPTH1-34 markedly suppressed endogenous mPTH1-84, but only the latter induced hypercalcemia. Daily PTH injection significantly increased both serum osteocalcin and mTRAP, while continuous PTH infusion showed a strong trend to stimulate mTRAP, with a slight but non-significant increase in osteocalcin. There were significant differences in BMD at all sites between animals treated with the same daily dose of intermittent and continuous hPTH1-34. Microcomputed tomography (µCT) analysis of the distal femurs revealed that hPTH1-34 infusion significantly decreased trabecular connectivity density (P<0·05). Thus, the murine bone response to continuous PTH infusion was quite different from that seen with daily PTH injection. Short-term infusion of hPTH1-34 appears to be a good model to study the mechanisms underlying the catabolic action of PTH in mice.

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Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice

Cited by 216 publications

References 41 publications

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

Persistent Downregulation of Calcium-Sensing Receptor mRNA in Rat Parathyroids when Severe Secondary Hyperparathyroidism Is Reversed by an Isogenic Kidney Transplantation

Short-term continuous infusion of human parathyroid hormone 1–34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice

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