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Endocrinology Jul 2022Rodent models are commonly used to evaluate parathyroid hormone (PTH) and PTH-related protein (PTHrP) ligands and analogues for their pharmacologic activities and...
Rodent models are commonly used to evaluate parathyroid hormone (PTH) and PTH-related protein (PTHrP) ligands and analogues for their pharmacologic activities and potential therapeutic utility toward diseases of bone and mineral ion metabolism. Divergence, however, in the amino acid sequences of rodent and human PTH receptors (rat and mouse PTH1Rs are 91% identical to the human PTH1R) can lead to differences in receptor-binding and signaling potencies for such ligands when assessed on rodent vs human PTH1Rs, as shown by cell-based assays in vitro. This introduces an element of uncertainty in the accuracy of rodent models for performing such preclinical evaluations. To overcome this potential uncertainty, we used a homologous recombination-based knockin (KI) approach to generate a mouse (in-host strain C57Bl/6N) in which complementary DNA encoding the human PTH1R replaces a segment (exon 4) of the murine PTH1R gene so that the human and not the mouse PTH1R protein is expressed. Expression is directed by the endogenous mouse promoter and hence occurs in all biologically relevant cells and tissues and at appropriate levels. The resulting homozygous hPTH1R-KI (humanized) mice were healthy over at least 10 generations and showed functional responses to injected PTH analog peptides that are consistent with a fully functional human PTH1R in target bone and kidney cells. The initial evaluation of these mice and their potential utility for predicting behavior of PTH analogues in humans is reported here.
Topics: Amino Acid Sequence; Animals; Ligands; Mice; Mice, Inbred C57BL; Mice, Transgenic; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Rats; Receptor, Parathyroid Hormone, Type 1; Receptors, Parathyroid Hormone; Signal Transduction
PubMed: 35460406
DOI: 10.1210/endocr/bqac054 -
The Journal of Clinical Endocrinology... Jun 2016Conventional management of hypoparathyroidism has focused upon maintaining the serum calcium with oral calcium and active vitamin D, often requiring high doses and... (Review)
Review
CONTEXT
Conventional management of hypoparathyroidism has focused upon maintaining the serum calcium with oral calcium and active vitamin D, often requiring high doses and giving rise to concerns about long-term consequences including renal and brain calcifications. Replacement therapy with PTH has recently become available. This paper summarizes the results of the findings and recommendations of the Working Group on Management of Hypoparathyroidism.
EVIDENCE ACQUISITION
Contributing authors reviewed the literature regarding physiology, pathophysiology, and nutritional aspects of hypoparathyroidism, management of acute hypocalcemia, clinical aspects of chronic management, and replacement therapy of hypoparathyroidism with PTH peptides. PubMed and other literature search engines were utilized.
EVIDENCE SYNTHESIS
Under normal circumstances, interactions between PTH and active vitamin D along with the dynamics of calcium and phosphorus absorption, renal tubular handing of those ions, and skeletal responsiveness help to maintain calcium homeostasis and skeletal health. In the absence of PTH, the gastrointestinal tract, kidneys, and skeleton are all affected, leading to hypocalcemia, hyperphosphatemia, reduced bone remodeling, and an inability to conserve filtered calcium. Acute hypocalcemia can be a medical emergency presenting with neuromuscular irritability. The recent availability of recombinant human PTH (1-84) has given hope that management of hypoparathyroidism with the missing hormone in this disorder will provide better control and reduced needs for calcium and vitamin D.
CONCLUSIONS
Hypoparathyroidism is associated with abnormal calcium and skeletal homeostasis. Control with calcium and active vitamin D can be a challenge. The availability of PTH (1-84) replacement therapy may usher new opportunities for better control with reduced supplementation requirements.
Topics: Calcium; Disease Management; Hormone Replacement Therapy; Humans; Hypocalcemia; Hypoparathyroidism; Parathyroid Hormone; Vitamin D
PubMed: 26938200
DOI: 10.1210/jc.2015-3910 -
F1000Research 2020Primary hyperparathyroidism is a hormonal disorder whose prevalence is approximately 1-2% in the United States of America. The disease has become more recognizable to... (Review)
Review
Primary hyperparathyroidism is a hormonal disorder whose prevalence is approximately 1-2% in the United States of America. The disease has become more recognizable to clinicians in an earlier phase and, at present, patients can be diagnosed with "classic", "normocalcemic", "normohormonal", or "mild, asymptomatic" primary hyperparathyroidism. Surgery, with a focused parathyroidectomy when possible, or a four-gland exploration, is the only way to cure the disease. Cure is determined by use of intra-operative parathyroid hormone monitoring with long-term cure rates ranging from 90-95%. Newer adjuncts to surgery include CT or PET imaging and near-infrared immunofluorescence. This article highlights updates in parathyroid disease and advances in parathyroid surgery; it does not provide a comprehensive summary of the disease process or a review of surgical indications, which can be found in the AAES guidelines or NIH Symposium on primary hyperparathyroidism.
Topics: Humans; Hyperparathyroidism, Primary; Monitoring, Intraoperative; Parathyroid Hormone; Parathyroidectomy
PubMed: 32148764
DOI: 10.12688/f1000research.21569.1 -
Orthopaedic Surgery Sep 2022To investigate the effect of intermittent parathyroid hormone (PTH) on gut microbiota (GM) in ovariectomized (OVX) osteoporotic rats.
OBJECTIVE
To investigate the effect of intermittent parathyroid hormone (PTH) on gut microbiota (GM) in ovariectomized (OVX) osteoporotic rats.
METHODS
Thirty female Sprague-Dawley rats were divided into three groups: sham-operation (SHAM) group, OVX group and PTH treatment group. After 3 months of treatment, the femurs, serum and feces were acquired for micro-CT, biochemical analysis and 16S rRNA sequencing, respectively. For 16S rRNA sequencing, after raw reads filtrated and chimera sequences removed, the clean reads were obtained. According to these clean reads, the operational taxonomic units (OTUs) were clustered. Venn diagram analysis was conducted to explore common and unique GM among the three groups. The α-diversity analysis including Shannon and Simpson indexes were used to evaluate the richness and diversity of the GM. The β-diversity analysis was performed to estimate the structure of GM. The metabolic function was predicted by Tax4Fun analysis.
RESULTS
With micro-CT and biochemical analysis, significant improvements were found in the PTH group compared with the OVX group. In Venn diagram analysis, more unique OTUs were found in the SHAM and PTH groups than the OVX group. According to the rank abundance curve, the SHAM and PTH groups had similar richness and evenness, which were higher than the OVX group. Simpson and Shannon indexes were higher in the SHAM and PTH groups compared with the OVX group, indicating that the SHAM and PTH groups had higher microbiota complexity than the OVX group. In β-diversity analysis, apparent separation was found in the OVX group from the PTH and SHAM groups, which suggested that osteoporosis is the critical factor influencing the GM composition and PTH treatment and can restore the structure of GM. Compared with the OVX group, treatment with PTH increased the abundances of GM which were reported to increase bone mass, such as Lactobacillus_reuteri, Muribaculaceae, Ruminococcaceae, and Clostridia, and inhibited the relative abundance of Rikenellaceae, which was reported to be potentially related to osteoporosis. GM function analysis showed that PTH could promote butyrate synthesis. In Tax4Fun analysis, the function of butanoate metabolism is more vital in the PTH group than the OVX and SHAM groups, suggesting PTH treatment could regulate microbial metabolic function, including butanoate metabolism.
CONCLUSION
Intermittent PTH can interact with GM through increasing the abundance of probiotics and reducing the abundance of the pathogenic bacteria to enhance the bone mass.
Topics: Animals; Female; Rats; Bone Density; Butyrates; Gastrointestinal Microbiome; Osteoporosis; Ovariectomy; Parathyroid Hormone; Rats, Sprague-Dawley; RNA, Ribosomal, 16S
PubMed: 35946436
DOI: 10.1111/os.13419 -
Endocrinology and Metabolism (Seoul,... Jun 2024Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder.... (Review)
Review
Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder. Levels of both hormones increase progressively in advanced CKD and can lead to damage in multiple organs. Secondary hyperparathyroidism (SHPT), characterized by parathyroid hyperplasia with increased PTH secretion, is associated with fractures and mortality. Emerging evidence suggests that these associations may be partially explained by PTH-induced browning of adipose tissue and increased energy expenditure. Observational studies suggest a survival benefit of PTHlowering therapy, and a recent study comparing parathyroidectomy and calcimimetics further suggests the importance of intensive PTH control. The mechanisms underlying the regulation of FGF23 secretion by osteocytes in response to phosphate load have been unclear, but recent experimental studies have identified glycerol-3-phosphate, a byproduct of glycolysis released by the kidney, as a key regulator of FGF23 production. Elevated FGF23 levels have been shown to be associated with mortality, and experimental data suggest off-target adverse effects of FGF23. However, the causal role of FGF23 in adverse outcomes in CKD patients remains to be established. Further studies are needed to determine whether intensive SHPT control improves clinical outcomes and whether treatment targeting FGF23 can improve patient outcomes.
Topics: Humans; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Parathyroid Hormone; Renal Insufficiency, Chronic; Hyperparathyroidism, Secondary; Animals
PubMed: 38752265
DOI: 10.3803/EnM.2024.1978 -
Endocrinology and Metabolism (Seoul,... Apr 2024The conventional treatment of hypoparathyroidism (HypoPT) includes active vitamin D and calcium. Despite normalization of calcium levels, the conventional treatment is... (Review)
Review
The conventional treatment of hypoparathyroidism (HypoPT) includes active vitamin D and calcium. Despite normalization of calcium levels, the conventional treatment is associated with fluctuations in calcium levels, hypercalciuria, renal impairment, and decreased quality of life (QoL). Replacement therapy with parathyroid hormone (PTH)(1-84) is an option in some countries. However, convincing beneficial effects have not been demonstrated, which may be due to the short duration of action of this treatment. Recently, palopegteriparatide (also known as TransCon PTH) has been marketed in Europe and is expected also to be approved in other countries. Palopegteriparatide is a prodrug with sustained release of PTH(1-34) designed to provide stable physiological PTH levels for 24 hours/day. A phase 3 study demonstrated maintenance of normocalcemia in patients with chronic HypoPT, with no need for conventional therapy. Furthermore, this treatment lowers urinary calcium and improves QoL. Another long-acting PTH analog with effects on the parathyroid hormone receptor (eneboparatide) is currently being tested in a phase 3 trial. Furthermore, the treatment of autosomal dominant hypocalcemia type 1 with a calcilytic (encaleret) is also being tested. All in all, improved treatment options are on the way that will likely take the treatment of HypoPT to the next level.
Topics: Humans; Hypoparathyroidism; Parathyroid Hormone; Hormone Replacement Therapy; Quality of Life; Calcium
PubMed: 38572533
DOI: 10.3803/EnM.2024.1916 -
Nature Reviews. Endocrinology Dec 2015Parathyroid hormone/parathyroid hormone-related protein receptor (PTH/PTHrP type 1 receptor; commonly known as PTHR1) is a family B G-protein-coupled receptor (GPCR)... (Review)
Review
Parathyroid hormone/parathyroid hormone-related protein receptor (PTH/PTHrP type 1 receptor; commonly known as PTHR1) is a family B G-protein-coupled receptor (GPCR) that regulates skeletal development, bone turnover and mineral ion homeostasis. PTHR1 transduces stimuli from PTH and PTHrP into the interior of target cells to promote diverse biochemical responses. Evaluation of the signalling properties of structurally modified PTHR1 ligands has helped to elucidate determinants of receptor function and mechanisms of downstream cellular and physiological responses. Analysis of PTHR1 responses induced by structurally modified ligands suggests that PTHR1 can continue to signal through a G-protein-mediated pathway within endosomes. Such findings challenge the longstanding paradigm in GPCR biology that the receptor is transiently activated at the cell membrane, followed by rapid deactivation and receptor internalization. Evaluation of structurally modified PTHR1 ligands has further led to the identification of ligand analogues that differ from PTH or PTHrP in the type, strength and duration of responses induced at the receptor, cellular and organism levels. These modified ligands, and the biochemical principles revealed through their use, might facilitate an improved understanding of PTHR1 function in vivo and enable the treatment of disorders resulting from defects in PTHR1 signalling. This Review discusses current understanding of PTHR1 modes of action and how these findings might be applied in future therapeutic agents.
Topics: Humans; Ligands; Osteoporosis; Parathyroid Hormone; Receptor, Parathyroid Hormone, Type 1; Signal Transduction
PubMed: 26303600
DOI: 10.1038/nrendo.2015.139 -
British Journal of Clinical Pharmacology Feb 2018In primary hyperparathyroidism (PHPT), bone loss results from the resorptive effects of excess parathyroid hormone (PTH). Under physiological conditions, PTH has actions... (Review)
Review
In primary hyperparathyroidism (PHPT), bone loss results from the resorptive effects of excess parathyroid hormone (PTH). Under physiological conditions, PTH has actions that are more targeted to homeostasis and to bone accrual. The predominant action of PTH, either catabolic, anabolic or homeostatic, can be understood in molecular and pharmacokinetic terms. When administered intermittently, PTH increases bone mass, but when present continuously and in excess (e.g. PHPT), bone loss ensues. This dual effect of PTH depends not only on the dosing regimen, continuous or intermittent, but also on how the PTH molecule interacts with various states of its receptor (PTH/PTHrP receptor) influencing downstream signalling pathways differentially. Altering the amino-terminal end of PTH or PTHrP could emphasize the state of the receptor that is linked to an osteoanabolic outcome. This concept led to the development of a PTHrP analogue that interacts preferentially with the transiently linked state of the receptor, emphasizing an osteoanabolic effect. However, designing PTH or PTHrP analogues with prolonged state of binding to the receptor would be expected to be linked to a homeostatic action associated with the tonic secretory state of the parathyroid glands that is advantageous in treating hypoparathyroidism. Ideally, further development of a drug delivery system that mimics the physiological tonic, circadian, and pulsatile profile of PTH would be optimal. This review discusses basic, translational and clinical studies that may well lead to newer approaches to the treatment of osteoporosis as well as to different PTH molecules that could become more advantageous in treating hypoparathyroidism.
Topics: Bone Density; Bone and Bones; Dose-Response Relationship, Drug; Drug Delivery Systems; Homeostasis; Humans; Hypoparathyroidism; Osteoporosis; Parathyroid Hormone; Protein Binding; Receptor, Parathyroid Hormone, Type 1; Translational Research, Biomedical
PubMed: 29049872
DOI: 10.1111/bcp.13455 -
International Journal of Molecular... Oct 2022Preclinical studies have shown that parathyroid hormone (PTH) loses its biological effects through oxidation. PTH can be oxidized at methionines 8 and 18. Three possible... (Review)
Review
Preclinical studies have shown that parathyroid hormone (PTH) loses its biological effects through oxidation. PTH can be oxidized at methionines 8 and 18. Three possible variations of oxidized PTH (oxPTH) exist: Met8(ox)PTH, Met18(ox)PTH, and Met8, Met18(di-ox)PTH. A recent study showed that Met18(ox)PTH retained biological activity and was able to upregulate gene expression, whereas Met8(ox)PTH and Met8, Met18(di-ox)PTH showed less or no biological activity. An earlier study likewise showed that the oxidation of Met18 has minor effects on the secondary structure of PTH, whereas the oxidation of Met8 causes substantial structural changes, consistent with another study showing that oxidization just at Met8 blocks the generation of the second messenger cAMP, whereas the effect of the oxidation of Met18 is much less potent in inhibiting cAMP formation. A considerable percentage of circulating PTH in chronic kidney disease (CKD) patients is oxidized. However, we do not know the relative amounts of the different forms of oxPTH with agonistic, partial agonistic, or even antagonistic biological actions in different CKD populations. This might explain different clinical findings in the different CKD populations analyzed so far. The currently available method that was used in these clinical studies just distinguishes between oxPTH and noxPTH without being able to differentiate between different forms of oxPTH. Only methods of PTH measurement that are able to differentiate between PTH forms (noxPTH, Met8(ox)PTH, Met18(ox)PTH, and Met8, Met18(di-ox)PTH) have the potential to improve patient care, because only these methods will definitively separate bioactive from non-bioactive PTH forms. Such methods need to be developed, validated, and used in prospective randomized clinical trials to define the potential value of bioactive PTH forms as a predictor of cardiovascular events, mortality, and bone turnover.
Topics: Humans; Parathyroid Hormone; Prospective Studies; Oxidation-Reduction; Renal Insufficiency, Chronic; Methionine
PubMed: 36293083
DOI: 10.3390/ijms232012228 -
Proceedings of the National Academy of... Feb 2019The parathyroid hormone (PTH) and its related peptide (PTHrP) activate PTH receptor (PTHR) signaling, but only the PTH sustains G-mediated adenosine 3',5'-cyclic...
The parathyroid hormone (PTH) and its related peptide (PTHrP) activate PTH receptor (PTHR) signaling, but only the PTH sustains G-mediated adenosine 3',5'-cyclic monophosphate (cAMP) production after PTHR internalization into early endosomes. The mechanism of this unexpected behavior for a G-protein-coupled receptor is not fully understood. Here, we show that extracellular Ca acts as a positive allosteric modulator of PTHR signaling that regulates sustained cAMP production. Equilibrium and kinetic studies of ligand-binding and receptor activation reveal that Ca prolongs the residence time of ligands on the receptor, thus, increasing both the duration of the receptor activation and the cAMP signaling. We further find that Ca allostery in the PTHR is strongly affected by the point mutation recently identified in the PTH (PTH) as a new cause of hypocalcemia in humans. Using high-resolution and mass accuracy mass spectrometry approaches, we identified acidic clusters in the receptor's first extracellular loop as key determinants for Ca allosterism and endosomal cAMP signaling. These findings coupled to defective Ca allostery and cAMP signaling in the PTHR by hypocalcemia-causing PTH suggest that Ca allostery in PTHR signaling may be involved in primary signaling processes regulating calcium homeostasis.
Topics: Allosteric Regulation; Animals; COS Cells; Calcium Signaling; Chlorocebus aethiops; Cyclic AMP; Humans; Hypocalcemia; Kinetics; Ligands; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Point Mutation; Protein Binding; Receptor, Parathyroid Hormone, Type 1
PubMed: 30718391
DOI: 10.1073/pnas.1814670116