Mechanistic Insights into Tanshinone IIA in the Amelioration of Post-Thyroidectomy Hypoparathyroidism.

BACKGROUND: Thyroidectomy causes impaired blood supply to the parathyroid glands, which leads to hypoparathyroidism. Tanshinone IIA (Tan IIA) is helpful in blood activation and cardiovascular protection. Therefore, the efficacy of Tan IIA in improving hypoparathyroidism was explored in this study. METHODS: New Zealand white rabbits were utilized to establish a unilateral parathyroid gland ischemia injury model. The model was created by selectively ligating the main blood supply vessel of one parathyroid gland, and the rabbits were then divided into three groups receiving 1, 5, and 10 mg/kg of Tan IIA. Serum calcium and parathyroid hormone (PTH) levels were measured using specialized assay kits. Immunohistochemistry was used to assess the microvessel density (MVD) in parathyroid glands. Western blotting (WB) was used to analyze protein expression related to the PI3K/AKT signaling pathway and the pathway-associated HIF-1α and VEGF. Moreover, MMP-2 and MMP-9 involved in angiogenesis were detected by WB. RESULTS: Tan IIA treatment effectively restored serum calcium and PTH levels in a dose-dependent manner. Notably, MVD in the parathyroid glands increased significantly, especially at higher doses. The Tan IIA treatment also elevated the p-PI3K/PI3K and p-AKT/AKT ratios, indicating that the PI3K/AKT pathway was reactivated. Moreover, Tan IIA significantly restored the decreased expression levels of VEGF and HIF-1α caused by parathyroid surgery. Additionally, Tan IIA increased MMP-2 and MMP-9 levels. CONCLUSION: Tan IIA activates the PI3K/AKT pathway, promotes angiogenesis by modulating VEGF, HIF-1α, MMP-2, and MMP-9, thereby further enhancing MVD within the parathyroid glands. This study demonstrates that Tan IIA improved post-thyroidectomy hypoparathyroidism.

Gallic acid pretreatment mitigates parathyroid ischemia-reperfusion injury through signaling pathway modulation.

Thyroid surgery often results in ischemia-reperfusion injury (IRI) to the parathyroid glands, yet the mechanisms underlying this and how to ameliorate IRI remain incompletely explored. Our study identifies a polyphenolic herbal extract-gallic acid (GA)-with antioxidative properties against IRI. Through flow cytometry and CCK8 assays, we investigate the protective effects of GA pretreatment on a parathyroid IRI model and decode its potential mechanisms via RNA-seq and bioinformatics analysis. Results reveal increased apoptosis, pronounced G1 phase arrest, and significantly reduced cell proliferation in the hypoxia/reoxygenation group compared to the hypoxia group, which GA pretreatment mitigates. RNA-seq and bioinformatics analysis indicate GA's modulation of various signaling pathways, including IL-17, AMPK, MAPK, transient receptor potential channels, cAMP, and Rap1. In summary, GA pretreatment demonstrates potential in protecting parathyroid cells from IRI by influencing various genes and signaling pathways. These findings offer a promising therapeutic strategy for hypoparathyroidism treatment.

Effect of fluoride on endocrine tissues and their secretory functions -- review.

The effects of fluoride on endocrine tissues has not been sufficiently explored to date. The current body of knowledge suggest significant effects of that mineral on reducing sex hormone levels, which may consequently impair fertility and disrupt puberty. The majority of studies confirm that sodium fluoride increases TSH levels and decreases the concentrations of T3 and T4 produced by the thyroid. Moreover, a correlation was observed between NaF and increased secretion of PTH by the parathyroid glands, without a significant impact on body calcium levels. Probably, fluoride may exert adverse effects on insulin levels, impairing pancreatic function and resulting in abnormal glucose tolerance. Observations also include decreased levels of cortisol secreted by the adrenal glands. In light of the few existing studies, the mechanism of fluoride toxicity on the endocrine system has been described.

Early response of the parathyroid gland to withdrawal of a calcimimetic compound in uremic rats.

Little is known about changes in parathyroid cells when calcimimetics are withdrawn. We examined the response of parathyroid glands to cinacalcet (Cina) withdrawal in uremic Sprague-Dawley rats fed a high-phosphate diet to develop secondary hyperparathyroidism and divided into groups treated with vehicle (UC), Cina, and Cina and maxacalcitol (Maxa), a vitamin D receptor activator (CiNa + Maxa). After 2 wk of treatment, vehicle and Cina were withdrawn and Maxa was continued. Rats were analyzed immediately (day 0) and 7 days (day 7) after withdrawal. The Cina and CiNa + Maxa groups had significantly lower parathyroid hormone (PTH) than the UC group on day 0, although PTH in the Cina group reached UC levels on day 7. On day 0, there were significantly more proliferating cell nuclear antigen-positive cells in the UC group compared with normal controls, and this increase was significantly suppressed in the Cina and CiNa + Maxa groups. On day 7, the Cina group, but not the CiNa + Maxa group, showed a significant increase in proliferating cell nuclear antigen-positive cells compared with the UC group. This increase was related to parathyroid cell diameter regression to UC levels, whereas combination treatment maintained diameter suppression. These results indicate that parathyroid growth activity is stimulated by Cina withdrawal, although the PTH level was not further increased. Continuous administration of Cina may be required for optimal control of secondary hyperparathyroidism, and simultaneous use of a vitamin D receptor activator may be advisable during Cina withdrawal.

Dietary protein and calcium modulate parathyroid vitamin D receptor expression in young ruminants.

For economic reasons and in order to minimize nitrogen excretion and thus pollution, the crude protein content in the diet of livestock animals should be as low as possible without negatively affecting the animals´ health and performance. As ruminants can efficiently use dietary protein because of the ruminohepatic circulation of urea, they are considered to cope more easily with such a feeding regime than monogastric animals. However, despite unaltered daily weight gain, massive changes in mineral homeostasis and vitamin D metabolism were observed with dietary protein reduction (N-) in young, growing goats. Serum concentrations of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) were decreased with a low N intake, even if calcium (Ca) was also restricted (Ca-). Interestingly, concentrations of cyclic adenosine monophosphate (cAMP) measured as an indirect assessment for the parathyroid hormone (PTH) activity were not affected by low protein. Therefore, it was hypothesized that the sensitivity of the parathyroid gland is modulated during these dietary interventions. Four groups of male German colored goats received a control (N+/Ca+), a reduced protein (N-/Ca+), a reduced Ca (N+/Ca-) or a reduced protein and Ca (N-/Ca-) diet. After six weeks we determined the expression of PTH, PTH receptor, Ca sensing receptor (CASR), vitamin D receptor (VDR), retinoid X receptor (RXRα), Klotho, fibroblast growth factor receptor 1c-splicing form, and the sodium-dependent Pi transporter (PiT1) in the parathyroid glands. Concentrations of cAMP were not affected, while those of Ca and 1,25-(OH)2D3were diminished and that of 25-hydroxyvitamin D3 was increased with N- feeding. The expression patterns of the described target genes were not altered. In contrast, animals fed the Ca- rations showed enhanced serum 1,25-(OH)2D3 and cAMP levels with no changes in blood Ca concentrations demonstrating an efficient adaptation. The mRNA expression of expression of VDR and CASR in the parathyroid gland was significantly diminished and RXRα, PTHR and PiT1 expression was elevated. Instead of the assumed desensitization of the parathyroid gland with N-, our results indicate elevated responsiveness to decreased blood Ca with feeding Ca-.

Influence of dialysate Ca concentrations on the therapeutic effects of etelcalcetide with concomitant drugs in patients with secondary hyperparathyroidism.

AIM: Secondary hyperparathyroidism (SHPT), a complication of haemodialysis, is commonly treated with calcimimetics. The impact of dialysates containing different calcium (Ca) concentrations on clinical efficacy of calcimimetics are unclear. We examined whether dialysate Ca concentrations influence the efficacy and dosing of etelcalcetide with concomitant drugs. METHODS: We performed post hoc analyses of a 52-week, open-label, multicentre study of etelcalcetide in Japanese SHPT patients to determine whether dialysate Ca influences the therapeutic effects of etelcalcetide with concomitant drugs. We evaluated the differences in serum intact parathyroid hormone (iPTH), corrected Ca (cCa) and phosphate levels among three dialysate Ca concentration groups (2.5, 2.75 or 3.0 mEq/L Ca). Tartrate-resistant acid phosphatase 5b (TRACP-5b) and bone alkaline phosphatase (BAP) levels were also compared. Since the dialysate Ca concentration may influence dose adjustment, we assessed the etelcalcetide and concomitant drug doses. RESULTS: There were no clinically meaningful differences in iPTH, cCa and phosphate levels among the 2.5, 2.75 and 3.0 mEq/L groups (n = 34, 64 and 35, respectively) over 52 weeks. At Week 52, more than 82%, 71% and 67% of patients had iPTH, cCa and phosphate levels within target ranges (60-240 pg/mL, 8.4-10.0 mg/dL and 3.5-6.0 mg/dL, respectively) across the three groups. TRACP-5b and BAP levels decreased by Week 52 regardless of dialysate Ca. Changes in etelcalcetide and concomitant drug doses were generally similar in each group. CONCLUSION: The efficacy and dosing of etelcalcetide with concomitant drugs were essentially unaffected by the dialysate Ca concentration. Patients showed improvements in bone hypermetabolism during treatment.

Mechanisms Involved in the Relationship between Low Calcium Intake and High Blood Pressure.

There is increasing epidemiologic and animal evidence that a low calcium diet increases blood pressure. The aim of this review is to compile the information on the link between low calcium intake and blood pressure. Calcium intake may regulate blood pressure by modifying intracellular calcium in vascular smooth muscle cells and by varying vascular volume through the renin-angiotensin-aldosterone system. Low calcium intake produces a rise of parathyroid gland activity. The parathyroid hormone increases intracellular calcium in vascular smooth muscles resulting in vasoconstriction. Parathyroidectomized animals did not show an increase in blood pressure when fed a low calcium diet as did sham-operated animals. Low calcium intake also increases the synthesis of calcitriol in a direct manner or mediated by parathyroid hormone (PTH). Calcitriol increases intracellular calcium in vascular smooth muscle cells. Both low calcium intake and PTH may stimulate renin release and consequently angiotensin II and aldosterone synthesis. We are willing with this review to promote discussions and contributions to achieve a better understanding of these mechanisms, and if required, the design of future studies.

Ultramicroscopic changes of rats parathyroid glands and thymus after single administration of cyclophosphamide at the different periods of observation.

OBJECTIVE: Introduction: Cyclophosphamide has wide spectrum usage as first-line drug in cancer chemotherapy that is why a detailed study of its effect on individual cell populations is of great interest for science and practice. The interaction of the nervous, immune and endocrine systems plays essential role in the homeostasis maintaining. The aim: This study aimed to investigate the ultramicroscopic changes that occur in the parathyroid glands and thymus of male rats after cyclophosphamide administration. PATIENTS AND METHODS: Materials and methods: Twenty-four WAG matured male rats were divided randomly into two groups. The first group served as control and was provided 0.9% soluble sodium chloride. The second group received cyclophosphamide in a dosage 200 mg/kg of body weight of animal by intramuscular single injection. All animals were sacrificed on the 7th and 30th day after injection. Parathyroid gland and thymus specimens were dissected out and processed for electron microscopy. RESULTS: Results: The results showed that cyclophosphamide exposure caused marked ultramicroscopic changes in rats parathyroid glands and thymus. On the 7th day after immunosuppression, the nuclei of parathyrocytes have deep wavy invaginations, amount of the organelles that participate in the protein synthesis is reduced to a minimum in the cytoplasm of the chief cells. Characteristic feature is the appearance of numerous plasma cells and active macrophages in thymus. There is a tendency to normalization of the parathyroid structure on the 30th day after administration of cyclophosphamide and reduction of mitotic activity of lymphocytes in thymus, which points to the development of involution process. CONCLUSION: Conclusions: This data can be successfully extrapolated from experimental animals to humans.

Effects of Long-Term Cinacalcet Administration on Parathyroid Gland in Hemodialysis Patients with Secondary Hyperparathyroidism.

BACKGROUND/AIM: Cinacalcet, an allosteric modulator of the calcium (Ca) sensing receptor, reduces the level of parathyroid hormone (PTH) in serum as well as parathyroid gland volume following administration in hemodialysis patients with secondary hyperparathyroidism, though long-term results are yet to be reported. METHODS: Serum parameters (n = 23), together with total parathyroid gland volume (n = 18), were determined in Japanese hemodialysis patients given cinacalcet treatment for 8 years. RESULTS: Following initiation of cinacalcet therapy, levels of serum Ca, phosphate, and intact PTH were significantly decreased. Furthermore, the baseline total volume of the parathyroid gland was 1,272 mm3 (496-2,836 mm3), which was then decreased after 6 months to 796 mm3 (377-1,146 mm3) and then to 332 mm3 (175-570 mm3) after 8 years. There was significant positive correlation between parathyroid gland volume at the start of cinacalcet treatment and reduction in volume during the 8 years cinacalcet treatment. The dose of phosphate binder was significantly decreased in a time-dependent manner after 8 years of cinacalcet treatment, likely because serum phosphate showed a progressive decrease with the treatment. CONCLUSION: In the present patients, long-term treatment with cinacalcet progressively decreased the total volume of parathyroid glands, as well as levels of intact PTH and phosphate in serum in a time-dependent manner. On the contrary, cinacalcet administration did not cause secondary failure or over-suppress the transition of parathyroid gland activity to hypoparathyroid status. These results suggest that cinacalcet treatment may postpone the need for parathyroidectomy and/or reduce its use even after long-term administration for up to 8 years.

Gcm2 regulates the maintenance of parathyroid cells in adult mice.

Glial cells missing homolog 2 (GCM2), a zinc finger-type transcription factor, is essential for the development of parathyroid glands. It is considered to be a master regulator because the glands do not form when Gcm2 is deficient. Remarkably, Gcm2 expression is maintained throughout the fetal stage and after birth. Considering the Gcm2 function in embryonic stages, it is predicted that Gcm2 maintains parathyroid cell differentiation and survival in adults. However, there is a lack of research regarding the function of Gcm2 in adulthood. Therefore, we analyzed Gcm2 function in adult tamoxifen-inducible Gcm2 conditional knockout mice. One month after tamoxifen injection, Gcm2-knockout mice showed no significant difference in serum calcium, phosphate, and PTH levels and in the expressions of calcium-sensing receptor (Casr) and parathyroid hormone (Pth), whereas Ki-67 positive cells were decreased and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) positive cell number did not change, as compared with those of controls. Seven months after tamoxifen injection, Gcm2-knockout mice showed shrinkage of the parathyroid glands and fewer parathyroid cells. A significant decrease was noted in Casr- and Pth-expressing cells and serum PTH and Ca levels, whereas serum phosphate levels increased, as compared with those of controls. All our results concluded that a reduction of Gcm2 expression leads to a reduction of parathyroid cell proliferation, an increase in cell death, and an attenuation of parathyroid function. Therefore, we indicate that Gcm2 plays a prominent role in adult parathyroid cell proliferation and maintenance.

Sevelamer hydrochloride suppresses proliferation of parathyroid cells during the early phase of chronic renal failure in rats.

AIM: We examined the effects of sevelamer on parathyroid cell proliferation and secondary hyperparathyroidism in rats following induction of early-phase of chronic renal failure (CRF) by unilateral ureteral obstruction (UUO). METHODS: For 5 days, rats in the control group received normal food, rats in the sevelamer group (SH) received control food plus 5% sevelamer, and rats in the low protein group (LP) received low protein food. Five rats of each group were killed at baseline (day 0). All other rats were given UUO, and five rats per group were killed on days 3, 7, 14, and 28 after UUO. Changes in body weight, serum phosphorus, calcium, intact-parathyroid hormone (i-PTH), creatinine (SCr), creatinine clearance rate (CCR), blood urea nitrogen (BUN), and 24-h urinary phosphorus were determined. Parathyroid tissues were removed for histological examination of proliferating cell nuclear antigen-positive (PCNA+) cells. RESULTS: Measurement of body weight, BUN, and SCr in the controls indicated successful establishment of this model of early-phase CRF. The controls also had remarkable proliferation of PCNA+ cells beginning on day 3, but this did not occur in the SH or LP groups. After 28 days, serum phosphorus had decreased more in the SH and LP groups than in the control group, and phosphorus excretion was much greater in the control group than in the SH and LP groups. The three groups had similar increases in serum i-PTH. CONCLUSION: Sevelamer rapidly lowered the serum phosphorus and inhibited the proliferation of PCNA+ cells in this experimental model of early-phase CRF.

Pharmacology of Parsabiv® (etelcalcetide, ONO-5163/AMG 416), a novel allosteric modulator of the calcium-sensing receptor, for secondary hyperparathyroidism in hemodialysis patients.

Etelcalcetide hydrochloride (Parsabiv®, ONO-5163/AMG 416) is an allosteric modulator of the calcium (Ca)-sensing receptor that was originally produced by KAI Pharmaceuticals Inc. (now Amgen Inc.). It has recently been approved as the first intravenous calcimimetic agent for secondary hyperparathyroidism (SHPT) in many countries. Etelcalcetide is an intravenous injectable drug that can be administered and eliminated through the dialysis circuit in chronic kidney disease patients. In the present study, we evaluated the in vitro pharmacological profile and in vivo parathyroid hormone (PTH)- and Ca-lowering activities of etelcalcetide in a rat 5/6 nephrectomy model of chronic renal insufficiency with SHPT. Etelcalcetide increased the intracellular Ca concentration in HEK-293T cells expressing human Ca-sensing receptor with an EC50 value (95% confidence interval) of 0.53 µM (0.28-1.0 µM) and suppressed PTH secretion from rat parathyroid gland cells with 0.36 µM (0.24-0.54 µM) by activating Ca-sensing receptor. The specificity of etelcalcetide was evaluated by examining its ability to stimulate or inhibit radioligand binding to a panel of 34 off-target proteins. There were no significant changes in the presence of 10 µM etelcalcetide. Furthermore, in a rat 5/6 nephrectomy model of chronic renal insufficiency with SHPT, single intravenous administration of etelcalcetide at 0.3, 1.0, and 3.0 mg/kg decreased plasma PTH and serum Ca levels. Taken together, the present findings identify etelcalcetide as a calcimimetic with potent PTH- and Ca-lowering effects via Ca-sensing receptor agonist activity.

NF-κB activation contributes to parathyroid cell proliferation in chronic kidney disease.

BACKGROUND: Secondary hyperparathyroidism is characterized by parathyroid gland (PG) hyperplasia, and excessive synthesis and secretion of parathyroid hormone (PTH). Reduced vitamin D receptor (VDR) density has shown to play an essential role in PG hyperplasia progression; nevertheless, its exact mechanism remains unclear. VDR has shown to suppress the inflammation mediator NF-κB-mediated gene transcription. The aim of this study is to examine whether NF-κB is involved in the pathogenesis of parathyroid hyperplasia. METHODS: 35 PGs was obtained from 10 maintenance hemodialysis patients who underwent parathyroidectomy surgery. 5/6-nephrectomized rats fed with a high-phosphate diet were divided into four groups: (1) Nx + vehicle group, treated with vehicle; (2) Nx + PDTC prevention group, treated with NF-κB inhibitor PDTC for 2 months; (3) Nx + PDTC therapy group, treated with PDTC for 1 month; (4) Nx + calcitriol group, treated with activated vitamin D calcitriol for 1 month. Ten sham-operated rats fed with normal-phosphate diet were used as a control group. Serum calcium, phosphorus, creatinine, Blood urea nitrogen (BUN), intact PTH and PG size in rats were measured. Proliferating cell nuclear antigen (PCNA), VDR, NF-κB of PGs were examined using immunohistochemistry and western blot. RESULTS: The activation of NF-κB pathway in the nodular hyperplasia gland was significantly increased compared with the diffuse hyperplasia gland found in hemodialysis patients. Markedly higher serum creatinine, BUN, phosphorus levels, serum iPTH levels and larger PGs were found in Nx rats fed with a high-phosphate diet compared to sham-operated rats. Also, PCNA levels and activation of NF-κB pathway in PGs were higher compared with the sham group, meanwhile the VDR levels decreased. Contrary, treating rats with PDTC and calcitriol notably reduced serum iPTH, expression of PCNA and activation of NF-κB pathway, and decreased the enlargement of PGs in those animals. CONCLUSIONS: NF-κB plays an important role in PG hyperplasia progression. VDR deficiency may be involved in the parathyroid gland hyperplasia through the activation of NF-κB pathway.

A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.

Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin.

Effect of the water fraction isolated from Fructus Ligustri Lucidi extract on bone metabolism via antagonizing a calcium-sensing receptor in experimental type 1 diabetic rats.

Our previous studies have demonstrated that the extract of Fructus Ligustri Lucidi (FLL) can maintain in vivo calcium homeostasis in aged and ovariectomized rats. This study was designed to elucidate the action of water fraction isolated from the FLL extract on bone metabolism and a calcium-sensing receptor (CaSR) in parathyroid glands and kidneys of diabetic rats. The streptozotocin-induced diabetic rats were treated with vehicle, FLL extract, and the water fraction (WF) isolated from the FLL extract for 4 weeks. Treatment with WF dramatically increased the serum levels of both calcium and parathyroid hormone and reduced urinary calcium excretion in diabetic rats as well as improved the pathological changes of trabecular bone as shown by the increased BA/TA, BMD/BV, and BV/TV. The mRNA expression of the calcium-binding protein 9k and protein expression of a vitamin D receptor (VDR) and plasma membrane Ca-ATPase in duodenum were significantly increased in diabetic rats after treatment with WF, which reduced the expression of CaSR in parathyroid gland and kidney as well as inhibited the up-regulation of VDR and 25-hydroxyvitamin D-24 hydroxylase expressions in the kidney of diabetic rats. This study reveals that the water fraction may be an active component of the FLL extract that exerts beneficial effects on improving bone metabolism via regulating vitamin D metabolism in kidney and vitamin D-dependent calcium transporters in duodenum as well as modulating the expression of CaSR in the parathyroid gland and kidneys.

Paricalcitol and cinacalcet have disparate actions on parathyroid oxyphil cell content in patients with chronic kidney disease.

The parathyroid oxyphil cell content increases in patients with chronic kidney disease (CKD), and even more in patients treated with the calcimimetic cinacalcet and/or calcitriol for hyperparathyroidism. Oxyphil cells have significantly more calcium-sensing receptors than chief cells, suggesting that the calcium-sensing receptor and calcimimetics are involved in the transdifferentiation of a chief cell to an oxyphil cell type. Here, we compared the effect of the vitamin D analog paricalcitol (a less calcemic analog of calcitriol) and/or cinacalcet on the oxyphil cell content in patients with CKD to further investigate the genesis of these cells. Parathyroid tissue from four normal individuals and 27 patients with CKD who underwent parathyroidectomy for secondary hyperparathyroidism were analyzed. Prior to parathyroidectomy, patients had received the following treatment: seven with no treatment, seven with cinacalcet only, eight with paricalcitol only, or cinacalcet plus paricalcitol in five. Oxyphilic areas of parathyroid tissue, reported as the mean percent of total tissue area per patient, were normal, 1.03; no treatment, 5.3; cinacalcet, 26.7 (significant vs. no treatment); paricalcitol, 6.9 (significant vs. cinacalcet; not significant vs. no treatment); and cinacalcet plus paricalcitol, 12.7. Cinacalcet treatment leads to a significant increase in parathyroid oxyphil cell content but paricalcitol does not, reinforcing a role for the calcium-sensing receptor activation in the transdifferentiation of chief-to-oxyphil cell type. Thus, two conventional treatments for hyperparathyroidism have disparate effects on parathyroid composition, and perhaps function. This finding is provocative and may be useful when evaluating future drugs for hyperparathyroidism.

The intriguing connections of leptin to hyperparathyroidism.

PURPOSE: Leptin has been implicated in bone metabolism, but the association with parathyroid gland function has not been fully clarified. This review aimed to summarize evidence of the association between leptin and hyperparathyroidism, both primary and secondary, elucidating the potential pathophysiologic and therapeutic consequences between leptin and parathyroid hormone, hopefully prompting the design of new studies. RESULTS: Experimental studies indicate a positive loop between leptin and parathyroid hormone in primary hyperparathyroidism. Dissimilar, parathyroid hormone seems to inhibit leptin expression in severe secondary hyperparathyroidism. Data from clinical studies indicate higher leptin levels in patients with primary hyperparathyroidism than controls, but no association between parathyroid hormone and leptin levels, as well as a minimal or neutral effect of parathyroidectomy on leptin levels in patients with primary hyperparathyroidism. Clinical data on secondary hyperparathyroidism, mainly derived from patients with chronic kidney disease, indicate a potential inverse association between leptin and parathyroid hormone in some, but not all studies. This relationship may be affected by the diversity of morbidity among these patients. CONCLUSIONS: Data from experimental studies suggest a different association between leptin and parathyroid hormone in primary and secondary hyperparathyroidism. Data from clinical studies are conflicting and potentially affected by confounders. More focused, well-designed studies are warranted to elucidate a potential association between leptin and parathyroid hormone, which may have specific clinical implications, i.e., targeting obesity and hyperleptinemia in patients with hyperparathyroidism.

The impact of calcineurin inhibitors on neutrophil gelatinase-associated lipocalin and fibroblast growth factor 23 in long-term kidney transplant patients.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL), a protein with bacteriostatic functions rapidly excreted from stimulated or damaged epithelial cells, is elevated in acute and chronic kidney disease. A calcineurin dependent signaling pathway for fibroblast growth factor 23 (FGF23) has been revealed, but the effect of calcineurin inhibitors (CNIs) on the levels of NGAL and markers of mineral metabolism in long-term kidney transplant patients has not been explored. METHODS: In a cross-sectional study, 39 patients who received a first kidney transplant more than 10 years ago were split into two groups based on whether (n=28) or not (n=11) they used CNIs. Only patients with well-functioning grafts defined as an estimated glomerular filtration rate ≥45 mL/min per 1.73 m2 were included. RESULTS: The median levels of NGAL, intact parathyroid hormone (iPTH), and iFGF23 were significantly higher in CNI users vs CNI nonusers, 167.0 (134.0-235.0) ng/mL vs 105.0 (91.3-117.0) ng/mL, P<.001, 13.8 (10.0-17.3) pmol/L vs 8.4 (6.4-9.9) pmol/L, P=.003, and 81.6 (56.4-116.5) pg/mL vs 61.8 (43.3-72.1) pg/mL, P=.04 respectively. CONCLUSIONS: The median levels of iFGF23 were higher in CNI users compared to CNI nonusers giving support to the notion of a CNI induced FGF23 resistance in the parathyroid. The net result of CNIs side effects needs to be further explored.

Two Techniques to Create Hypoparathyroid Mice: Parathyroidectomy Using GFP Glands and Diphtheria-Toxin-Mediated Parathyroid Ablation.

Hypoparathyroidism (HP) is a disorder characterized by low levels of PTH which lead to hypocalcemia, hyperphosphatemia, and low bone turnover. The most common cause of the disease is accidental removal of the parathyroid glands during thyroid surgery. Novel therapies for HP are needed, but testing them requires reliable animal models of acquired HP. Here, we demonstrate the generation of two mouse models of acquired HP. In the GFP-PTX model, mice with green fluorescent protein (GFP) expressed specifically in the parathyroids (PTHcre-mTmG) were created by crossing PTHcre+ mice with Rosa-mTmGfl/fl mice. Green fluorescing parathyroid glands are easily identified under a fluorescence dissecting microscope and parathyroidectomy is performed in less than 20 min. After fluorescence-guided surgery, mice are profoundly hypocalcemic. Contrary to the traditional thyro-parathyroidectomy, this precise surgical approach leaves thyroid glands and thyroid function intact. The second model, which does not require surgery, is based on a diphtheria-toxin approach. PTHcre-iDTR mice, which express the diphtheria toxin (DT) receptor specifically in the parathyroids, were generated by crossing the inducible DTR mouse with the PTHcre mouse. Parathyroid cells are thus rendered sensitive to diphtheria toxin (DT) and can be selectively destroyed by systemically injecting mice with DT. The resulting hypocalcemic phenotype is stable.