糖尿病大鼠骨代谢的变化

目的研究糖尿病早期骨代谢改变。方法测定６周实验性糖尿病（ＳＴＺ－ＤＭ）大鼠空腹血糖、ＨｂＡ１ｃ、胰岛素、钙离子浓度、骨钙素、降钙素、ＰＴＨ和维生素Ｄ３。收集２４ｈ尿，测定白蛋白、肌酐、吡啶酚。结果糖尿病大鼠与正常对照组相比，血清钙浓度显著升高［（１３５．８５±１１．２８）对（１１７．２１±６．５２）ｍｇ／Ｌ，Ｐ＜０．０１］，骨钙素水平升高［（０．０７±０．０４）对（０．０５±０．０１）ｎｇ／ｍｌ，Ｐ＜０．０５］，维生素Ｄ３水平显著降低［（７．６３±１．８８）对（１１．５５±４．１１）ｎｇ／ｍｌ，Ｐ＜０．０５］，尿吡啶酚／肌酐显著降低［（４．７９±０．７５）对（７５．８４±６０．６７）ｎｍｏｌ／ｍｍｏｌ，Ｐ＜０．０１］；而血清降钙素和甲状旁腺素水平改变无统计学意义。结论糖尿病状态下存在骨代谢异常，主要表现为维生素Ｄ３降低、骨钙素升高及尿吡啶酚水平降低。糖尿病性骨质疏松可能与维生素Ｄ３水平降低及由于胰岛素缺乏所致的骨胶原合成障碍有关     

Immunohistochemical localization of parathyroid hormone/parathyroid hormone-related peptide receptor in rat tibiae

After developing antisera against the extracellular part of the parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH/PTHrP receptor), we examined the receptor's localization in rat tibiae. Immunoreactivity for the PTH/PTHrP receptor was intense on chondrocytes in the late proliferating zone and the early hypertrophic zone in the growth plate. Active bone surface osteoblasts also showed intense immunoreactivity for the PTH/PTHrP receptor along their plasma membranes. In other osteoblastic cells, the PTH/PTHrP receptor was detected on spindle-shaped mononuclear cells located between the blood vessels and osteoblasts, osteocytes, and flat osteoblasts. Some stromal cells in bone marrow and bone marrow cells with a round profile also showed immunoreactivity. However, we could not detect immunoreactivity on osteoclasts. It is still unclear whether the PTH/PTHrP receptor exists on osteoclast precursor cells. However, these data confirmed the stage-dependent changes in PTH/PTHrP receptor levels on chondrocytes in the growth plate and on osteoblastic cell lineage, suggesting that the effect of PTH and/or PTHrP on mineral homeostasis as well as on skeletal growth and development is well mediated by chondrocytes and osteoblasts.This study was partly supported by a grant from the Japanese Ministry of Education, Science and Culture to I.K. (No. 06771577) and O.H. (No. 06404063)     

Blood-pressure-independent wall thickening of intramyocardial arterioles in experimental uraemia: evidence for a permissive action of PTH

BACKGROUND.: Abnormalities in cardiovascular structures, e.g. LV hypertrophyand thickening of vessels (arteries, arterioles, veins) arehallmarks of renal failure. They are in part independent ofelevated blood pressure. Parathyroid hormone (PTH) has beenshown to affect cardiac function and has also been identifiedas a permissive factor in the genesis of cardiac fibrosis. PURPOSE OF THE STUDY.: The present study in rats with experimental renal failure wasdesigned to examine whether PTH was permissive for wall thickeningof intramyocardial arterioles as well. METHODS.: Male SD rats were sham operated or sub-totally nephrectomizedand maintained for 2 weeks. Subgroups of subtotally nephrectomized(SNX) rats were parathyroidectomized (PTX). Saline or rat 1,34 PTH was administered by osmotic minipump. Eucalcaemia wasmaintained in PTX animals by a high-calcium diet (3%). Serumcalcium was not statistically different between the groups.After perfusion fixation, intramyocardial arterioles were assessedusing stereological techniques (wall thickness; wall/lumen ratio;minimal lumen diameter; length density). RESULTS.: In random samples of the left ventricle, wall thickness of arterioleswas 2.2±0.25 µm in sham-op controls and 2.76±0.41in SNX (n=at least 8 animals per group). SNX-PTX animals+solventdid not differ significantly from sham-op controls (2.08±0.42µm), while SNX-PTX animals+PTH had values not significantlydifferent from SNX (2.59±0.54 µm). Differencesin wall thickness were not paralleled by differences in systolicblood pressure (sham-op 110±13.3 mmHg; SNX 138±8.4mmHg, SNX PTX+solvent 142±5.2 mmHg; SNX-PTX+PTH 148±5.7mmHg). PTH treated animals showed signs of marked vascular smooth-musclecell and endothelial-cell activation. CONCLUSIONS.: The data suggest that wall thickening of intramyocardial arteriolesin short-term experimental uraemia is dependent upon the presenceof PTH (permissive effect).     

Changes in serum fibroblast growth factor 2 in patients with glucocorticoid-induced osteoporosis treated with human parathyroid hormone (1–34)

Since the ability of parathyroid hormone (PTH) to increase osteoblast maturation and activity is associated with basic fibroblast growth factor (bFGF) we determined the changes in serum bFGF levels in patients treated with human parathyroid hormone (hPTH) (1–34) for 12 months and 12 months follow up. All studied subjects (n=51) had postmenopausal osteoporosis, had been receiving long-term treatment with glucocorticoid plus estrogen or estrogen/progesterone and were randomly allocated either to a group receiving hPTH, 400 U/day (n=28), or to a control group (n=23). Osteocalcin (OST), bone-specific alkaline phosphatase (BSAP) and bFGF were monitored at the baseline, every 3 months for 18 months, and at 24 months. In the hPTH group, OST increased by more than 150% above baseline at 3 months and was maintained at this level throughout the treatment period. BSAP had increased more than 80% over the baseline level at 3 months and was maintained at 90% above baseline for the next 9 months. bFGF levels had increased by 45% at 3 months, 60% at 6 to 9 months (P<0.05) and had increased more than 90% from baseline by 12 months (P<0.05). We found that daily hPTH injections increased bFGF levels. These results support the hypothesis that up-regulation of bFGF could play a role in the osteoblastic response to PTH.     

Thapsigargin shifts the CA set point of parathyroid cells to lower extracellular [CA]

The hypothesis that cytosolic calcium concentration ([Ca²⁺ _cyt]) is the primary regulator of parathyroid hormone (PTH) secretion is supported by a number of studies that show an inverse relationship between them. One agent shown to inhibit PTH secretion is thapsigargin, a sesquiterpene lactone that raises [Ca²⁺ _cyt] by inhibiting the Ca-ATPase that pumps Ca²⁺ from the cytosol into the lumen of the endoplasmic reticulum. Thapsigargin may act on the parathyroid cell other than to inhibit the Ca-ATPase, however, in ways that might also affect PTH secretion. We have tested its effects on functional parameters, such as protein synthesis, the exocytic machinery, and the ability of parathyroid cells to respond to different concentrations of extracellular Ca²⁺ ([Ca²⁺ _ex]). In particular, we have determined whether the inhibition of PTH secretion by thapsigargin is independent of or is modulated by changes in [Ca²⁺ _ex]. The results revealed no effects of thapsigargin on protein synthesis or the exocytic mechanisms within 2 h of treatment, and showed that [Ca²⁺ _ex] can modulate PTH secretion in the presence of thapsigargin. Its inhibition of PTH secretion, therefore, appears to rest on its ability to shift [Ca²⁺ _cyt] to higher levels, but the possibility that it interacts with the Ca receptor has not been eliminated. The results support the hypothesis that the primary regulator of steady-state PTH secretion is [Ca²⁺ _cyt].     

Comparison of dried plum supplementation and intermittent PTH in restoring bone in osteopenic orchidectomized rats

Summary Bone loss was confirmed after 90 days in 50 6-month-old male Sprague Dawley rats that were sham-operated or orchidectomized (ORX). In this study, we have shown that dried plum (DP) has potent effects on bone in terms of bone mass, microarchitecture, and strength in osteopenic male rats. Although these changes may be mediated through the suppression of bone resorption, the fact that the restoration in some of the bone structural and biomechanical parameter shares some similarities with parathyroid hormone (PTH) should not be overlooked. Further investigation is needed on a mechanistic level to clarify the influence of DP on bone metabolism. Introduction This study was designed to investigate the extent to which DP reverses bone loss in osteopenic ORX rats and to compare its effects to PTH. Materials and methods Fifty, 6-month-old male Sprague Dawley rats were sham-operated or ORX, and bone loss was confirmed after 90 days. The ORX groups were assigned to control (AIN-93M) diet, 25% DP diet, or PTH (80 μg/kg) for 90 days. Results DP induced an 11% increase in vertebral and femoral BMD compared to ORX-controls. BMD in the PTH-treated group was increased by 20.7% (vertebra) and 17.9% (femur). Vertebral trabecular bone volume (BV/TV) and number were increased by DP and trabecular separation was decreased compared to controls, which were similar to PTH. Alterations in trabecular bone of the femur were similar to those in the vertebra, but DP did not restore BV/TV to the same extent. Cortical thickness was improved by DP and further enhanced by PTH. DP tended to decrease urinary deoxypyridinoline and calcium, but did not alter alkaline phosphatase or osteocalcin. Conclusion We conclude that though the degree of improvement was not equivalent to PTH with regard to all parameters, DP reverses bone loss due to ORX and the mechanisms should be further investigated.     

Inter-relations between the calcium set-points of Parfitt and Brown in primary hyperparathyroidism: a sequential citrate and calcium clamp study

Abstract. The objective of the present study was to compare the calcium set-points of E. M. Brown and A. M. Parfitt obtained by sequential citrate and calcium clamp in patients with primary hyperparathyroidism and healthy controls. Twenty-six patients with primary hyperparathyroidism were investigated and compared to 22 healthy volunteers. All participants were investigated by sequential calcium lowering and raising comprising the following four phases: Phase (1) blood ionized calcium lowering of about 0·20 mmol l^-1; phase (2) steady-state (relative) hypocalcaemia of blood ionized calcium 0·20 mmol l^-1 below baseline; phase (3) blood ionized calcium is raised to about 0·20 mmol l^-1 above baseline; and phase (4) (relative) hypercalcaemia of blood ionized calcium 0·20 mmol l^-1 above baseline. Serum parathyroid hormone (1–84) was measured by an immunoradiometric assay. Blood ionized calcium was measured by a calcium selective electrode. We found the calcium set-points of Parfitt to be 1·42 mmol l^-1 (SD 0·12, n= 52) vs. 1·25 mmol l^-1 (SD 0·04, n= 44) in patients and controls, respectively (P < 0·001). The calcium set-points of Brown were 1·32 mmol l^-1 (SD 0·10, n= 26) vs. 1·13 mmol l^-1 (SD 0·04, n= 22), respectively (P < 0·001). By comparing the calcium set-points of Parfitt and Brown, a strikingly good correlation was observed, in patients (r= 0·91, P < 0·001) and in controls (r= 0·85, P < 0·001). We demonstrate in this paper in vivo that Brown's and Parfitt's calcium set-points are raised in primary hyperparathyroidism and return to normal following parathyroidectomy. The values for Brown's and Parfitt's calcium set-points are significantly different, but strikingly well correlated, supporting the view that Brown and Parfitt describe two different points on the same sigmoidal curve, corresponding to 50% and about 85% inhibition of PTH maximum, respectively. The mathematical form of the sigmoidal curve between blood ionized calcium and parathyroid hormone is very similar in primary hyperparathyroidism and normal humans.     

Chicken Parathyroid Hormone Gene Expression in Response to Gastrin,Omeprazole, Ergocalciferol,and Restricted Food Intake

Treatment with omeprazole, a long-acting proton pump inhibitor of acid secretion, induces hypergastrinemia. In chickens, omeprazole induces growth not only of the acid-producing mucosa (probably reflecting the trophic action of gastrin), but also of the parathyroid glands (hypertrophy + hyperplasia), while suppressing bone density and body weight gain without affecting blood calcium. The first part of the present study was concerned with the effect of omeprazole, ergocalciferol (vitamin D₂), and restricted food intake on the gene expression of parathyroid hormone (PTH) in the parathyroid glands of the chicken. Chickens were treated with omeprazole (400 μmol/kg/day, I.M.), food restriction, omeprazole + food restriction, ergocalciferol (250 000 IU/kg/day, S.C.), or ergocalciferol + omeprazole for 5 weeks. The weight gain of the chickens was monitored, and the weights of the parathyroid glands and femurs were determined at sacrifice. PTH mRNA in the parathyroid glands was analyzed by Northern blot. The second part of the study examined the effect of 3 weeks of continuous gastrin infusion (chicken gastrin 20–36, 5 nmol/kg/hour, S.C.) on the expression of PTH mRNA in the parathyroid glands. Omeprazole reduced the body weight and femur density (ash weight per volume) while greatly increasing the weight of the parathyroid glands and the PTH gene expression. Food restriction alone and ergocalciferol alone (at a dose that raised blood Ca²⁺) were without effect, but food restriction greatly enhanced the omeprazole-evoked increase in parathyroid gland weight and PTH gene expression. Gastrin increased the weight of the parathyroid glands and reproduced the effect of omeprazole on PTH gene expression. Hence, it seems likely that the effect of omeprazole reflects the ensuing hypergastrinemia. Received: 6 August 1996 / Accepted: 23 April 1997     

A case of polycythemia vera complicated by chronic renal failure under hemodialysis requiring parathyroidectomy for secondary hyperparathyroidisim

A case of polycythemia vera complicated by chronic renal failure under maintenance hemodialysis requiring parathyroidectory (PTH) for secondary hyperparathyroidism (2° HPT) is reported. A 62 year old female presented with 75000 white blood cells (WBC)/μl, 703×10⁴ red blood cells (RBC)/μl, 23×10⁴ platelets (PLT)/μl, hyperuricemia and hypertension in 1970 and the diagnosis of polycythemia vera was made. Hemodialysis was started in October 1974 for chronic renal failure. Blood cells in peripheral blood rapidly decreased in number after the beginning of dialysis, reaching the level of 10000∼20000 WBC/μl, and 150∼250×10⁴RBC/μl. In August 1988, marked bone resorption in X-ray picture and high serum alkaline phosphatase and parathyroid hormone (PTH) noted along with 17400 WBC/μl, 370×10⁴RBC/μl and 35.9×10⁴PLT/μl. After subtotal PTX removing 3.21g parathyroid gland, serum PTH rapidly fell. At 3 months after PTX, WBC rose to 23600/μl, RBC 372×10⁴/μl and PLT 94.0×10⁴/μl. At 6 months, WBC was to 31000/μl, RBC 429×10⁴/μl and PLT 78.0×10⁴/μl, suggesting an inhibitory action of PTH on not only RBC, but also WBC and PLT.     

Anabolic actions of PTH in murine models: two decades of insights

Parathyroid hormone (PTH) is produced by the parathyroid glands in response to low serum calcium concentrations where it targets bones, kidneys, and indirectly, intestines. The N-terminus of PTH has been investigated for decades for its ability to stimulate bone formation when administered intermittently (iPTH) and is used clinically as an effective anabolic agent for the treatment of osteoporosis. Despite great interest in iPTH and its clinical use, the mechanisms of PTH action remain complicated and not fully defined. More than 70 gene targets in more than 90 murine models have been utilized to better understand PTH anabolic actions. Because murine studies utilized wild-type mice as positive controls, a variety of variables were analyzed to better understand the optimal conditions under which iPTH functions. The greatest responses to iPTH were in male mice, with treatment starting later than 12 weeks of age, a treatment duration lasting 5–6 weeks, and a PTH dose of 30–60 μg/kg/day. This comprehensive study also evaluated these genetic models relative to the bone formative actions with a primary focus on the trabecular compartment revealing trends in critical genes and gene families relevant for PTH anabolic actions. The summation of these data revealed the gene deletions with the greatest increase in trabecular bone volume in response to iPTH. These included PTH and 1-α-hydroxylase (Pth;1α(OH)ase, 62-fold), amphiregulin (Areg, 15.8-fold), and PTH related protein (Pthrp, 10.2-fold). The deletions with the greatest inhibition of the anabolic response include deletions of: proteoglycan 4 (Prg4, −9.7-fold), low-density lipoprotein receptor-related protein 6 (Lrp6, 1.3-fold), and low-density lipoprotein receptor-related protein 5 (Lrp5, −1.0-fold). Anabolic actions of iPTH were broadly affected via multiple and diverse genes. This data provides critical insight for future research and development, as well as application to human therapeutics. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).