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Nature Communications Feb 2022Parathyroid hormone (PTH) plays crucial role in maintaining calcium and phosphorus homeostasis. In the progression of secondary hyperparathyroidism (SHPT), expression of...
Parathyroid hormone (PTH) plays crucial role in maintaining calcium and phosphorus homeostasis. In the progression of secondary hyperparathyroidism (SHPT), expression of calcium-sensing receptors (CaSR) in the parathyroid gland decreases, which leads to persistent hypersecretion of PTH. How to precisely manipulate PTH secretion in parathyroid tissue and underlying molecular mechanism is not clear. Here, we establish an optogenetic approach that bypasses CaSR to inhibit PTH secretion in human hyperplastic parathyroid cells. We found that optogenetic stimulation elevates intracellular calcium, inhibits both PTH synthesis and secretion in human parathyroid cells. Long-term pulsatile PTH secretion induced by light stimulation prevented hyperplastic parathyroid tissue-induced bone loss by influencing the bone remodeling in mice. The effects are mediated by light stimulation of opsin expressing parathyroid cells and other type of cells in parathyroid tissue. Our study provides a strategy to regulate release of PTH and associated bone loss of SHPT through an optogenetic approach.
Topics: Bone and Bones; Calcium; Homeostasis; Humans; Hyperparathyroidism; Hyperparathyroidism, Secondary; Hyperplasia; Optogenetics; Parathyroid Glands; Parathyroid Hormone; Receptors, Calcium-Sensing
PubMed: 35140213
DOI: 10.1038/s41467-022-28472-9 -
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 -
The Journal of Clinical Endocrinology... Mar 2021Exposed surfaces of mammals are colonized with 100 trillion indigenous bacteria, fungi, and viruses, creating a diverse ecosystem known as the human microbiome. The gut... (Review)
Review
Exposed surfaces of mammals are colonized with 100 trillion indigenous bacteria, fungi, and viruses, creating a diverse ecosystem known as the human microbiome. The gut microbiome is the richest microbiome and is now known to regulate postnatal skeletal development and the activity of the major endocrine regulators of bone. Parathyroid hormone (PTH) is one of the bone-regulating hormone that requires elements of the gut microbiome to exert both its bone catabolic and its bone anabolic effects. How the gut microbiome regulates the skeletal response to PTH is object of intense research. Involved mechanisms include absorption and diffusion of bacterial metabolites, such as short-chain fatty acids, and trafficking of immune cells from the gut to the bone marrow. This review will focus on how the gut microbiome communicates and regulates bone marrow cells in order to modulate the skeletal effects of PTH.
Topics: Animals; Bone Development; Bone Marrow; Bone Marrow Cells; Bone Remodeling; Bone and Bones; Gastrointestinal Microbiome; Humans; Parathyroid Hormone
PubMed: 33254225
DOI: 10.1210/clinem/dgaa895 -
International Journal of Surgery... Oct 2019Thermal ablation and parathyroidectomy (PTX) have been recommended for patients with secondary hyperparathyroidism (SHPT). However, it is uncertain which is the better... (Comparative Study)
Comparative Study Review
OBJECTIVE
Thermal ablation and parathyroidectomy (PTX) have been recommended for patients with secondary hyperparathyroidism (SHPT). However, it is uncertain which is the better method. The aim of the present meta-analysis was to evaluate the efficacy and surgical complications of the two treatment methods.
METHODS
The following databases were searched from inception to December 31, 2018: PubMed, EMBASE, the Cochrane Library, CNKI, and Wanfang. Eligible studies comparing thermal ablation and PTX for SHPT were included. Data were analysed using Review Manager Version 5.3.
RESULTS
Six studies were included in the meta-analysis. Four cohort studies and two randomized controlled trials involving 326 patients with SHPT were identified. There was no difference concerning parathyroid hormone (PTH) levels (MD 58.04, 95% CI -17.60-133.68, P = 0.13), calcium levels (MD -0.07, 95% CI -0.17-0.04, P = 0.21), phosphorus levels (MD 0.21, 95% CI -0.18-0.61, P = 0.29), or hoarseness (OR 0.53, 95% CI 0.24-1.16, P = 0.11) between the two surgical methods. Compared with PTX, thermal ablation reduced the risk of hypocalcaemia (OR 0.23, 95% CI 0.11-0.47, P < 0.01). However, thermal ablation increased the risk of SHPT persistence and/or recurrence compared with PTX (OR 4.24, 95% CI 1.44-15.76, P = 0.03).
CONCLUSION
Thermal ablation and PTX were effective surgical approaches for SHTP. Thermal ablation reduced the risk of hypocalcaemia and increased the risk of SHPT persistence and recurrence. More large multicentre randomized controlled trials are necessary to confirm the conclusions.
Topics: Ablation Techniques; Adult; Aged; Cohort Studies; Humans; Hyperparathyroidism, Secondary; Hypocalcemia; Middle Aged; Parathyroid Hormone; Parathyroidectomy
PubMed: 31404676
DOI: 10.1016/j.ijsu.2019.08.004 -
Nature Communications Apr 2020Antibodies conjugated to bioactive compounds allow targeted delivery of therapeutics to cell types of choice based on that antibody's specificity. Here we develop a new...
Antibodies conjugated to bioactive compounds allow targeted delivery of therapeutics to cell types of choice based on that antibody's specificity. Here we develop a new type of conjugate that consists of a nanobody and a peptidic ligand for a G protein-coupled receptor (GPCR), fused via their C-termini. We address activation of parathyroid hormone receptor-1 (PTHR1) and improve the signaling activity and specificity of otherwise poorly active N-terminal peptide fragments of PTH by conjugating them to nanobodies (VHHs) that recognize PTHR1. These C-to-C conjugates show biological activity superior to that of the parent fragment peptide in vitro. In an exploratory experiment in mice, a VHH-PTH peptide conjugate showed biological activity, whereas the corresponding free peptide did not. The lead conjugate also possesses selectivity for PTHR1 superior to that of PTH(1-34). This design approach, dubbed "conjugation of ligands and antibodies for membrane proteins" (CLAMP), can yield ligands with high potency and specificity.
Topics: Amino Acid Sequence; Animals; Female; HEK293 Cells; Humans; Ligands; Mice; Models, Molecular; Parathyroid Hormone; Peptides; Protein Binding; Receptor, Parathyroid Hormone, Type 1; Receptors, G-Protein-Coupled; Single-Domain Antibodies
PubMed: 32350260
DOI: 10.1038/s41467-020-15884-8 -
Surgery Jan 2021We sought to better understand the experience of patients with transient hypoparathyroidism using patient interviews and quality of life surveys.
BACKGROUND
We sought to better understand the experience of patients with transient hypoparathyroidism using patient interviews and quality of life surveys.
METHODS
This is a prospective analysis of 62 patients after total thyroidectomy at a high-volume institution. Semistructured patient interviews and quality of life surveys were conducted preoperatively and postoperatively at 2 weeks, 6 weeks, 6 months, and 1 year and compared based on postoperative parathyroid hormone levels.
RESULTS
Postoperative parathyroid hormone levels were <10 pg/mL in 32% of patients (n = 20), 10 to 20 pg/mL in 19% (n = 12), and >20 pg/mL in 48% (n = 30). Hypocalcemic symptoms at 2 weeks were reported in 28 of 55 patients (51%), but patients felt "well prepared" and reported it "wasn't a big deal." If symptoms persisted at 6 weeks, they became more bothersome. At 6 months and 1 year, patients reported calcium supplementation prevented most symptoms and did not interfere with daily activities. Quality of life as measured by the European Organization for Research and Treatment of Cancer and the 12-Item Short Form Survey demonstrated a slight improvement at 1 year postoperatively regardless of parathyroid hormone level.
CONCLUSION
Early postoperative transient hypoparathyroidism is common but when appropriately managed did not have a substantial negative impact on the overall quality of life.
Topics: Adult; Aged; Calcium; Female; Follow-Up Studies; Humans; Hypocalcemia; Hypoparathyroidism; Male; Middle Aged; Parathyroid Glands; Parathyroid Hormone; Postoperative Complications; Preoperative Period; Prospective Studies; Qualitative Research; Quality of Life; Risk Factors; Thyroid Neoplasms; Thyroidectomy; Young Adult
PubMed: 32654859
DOI: 10.1016/j.surg.2020.04.029 -
International Journal of Hyperthermia :... 2022To investigate the efficacy of radiofrequency ablation (RFA) as a treatment option for primary hyperparathyroidism (pHPT) and risk factors for postablative eucalcemic...
OBJECTIVE
To investigate the efficacy of radiofrequency ablation (RFA) as a treatment option for primary hyperparathyroidism (pHPT) and risk factors for postablative eucalcemic parathyroid hormone elevation (ePTH).
METHODS
This retrospective study included 51 patients with pHPT who underwent RFA. The patients were divided into the ePTH and normal PTH groups, based on the serum intact parathyroid hormone (iPTH) level one month after ablation. Serum iPTH, calcium, and phosphorus levels, and the volume reduction rates (VRR) of the parathyroid glands were compared between the groups at each follow-up point. Risk factors for ePTH at one month after ablation were examined.
RESULTS
After RFA, one (2%) patient had persistent pHPT, and 50 (98%) patients were cured. The incidence rates of ePTH at 1, 3, 6, and 12 months were 48%, 30%, 20%, and 16%, respectively. Serum iPTH levels in the ePTH group were higher than those in the normal PTH group at each follow-up point (all < 0.05), except 1 day after ablation ( > 0.05). Serum calcium and phosphorus levels, and the VRR of the glands were comparable in both groups at each follow-up point (all > 0.05), except for calcium levels 3 days after RFA ( < 0.05). Baseline iPTH (odds ratio, 1.067; = 0.045) and calcium (odds ratio, 3.923; = 0.038) levels were independent risk factors for ePTH 1 month after RFA.
CONCLUSIONS
RFA is safe and effective for the treatment of pHPT. Moreover, ePTH occurrence after RFA was associated with baseline iPTH and calcium levels and did not increase the risk of recurrent pHPT.
Topics: Calcium; Humans; Hyperparathyroidism, Primary; Parathyroid Hormone; Parathyroidectomy; Radiofrequency Ablation; Retrospective Studies; Risk Factors
PubMed: 35285391
DOI: 10.1080/02656736.2022.2047231 -
Journal of Nutritional Science 2023It is currently debated whether vitamin D requirements during pregnancy differ from those during non-gravid states. In current analyses, we aimed to determine the best...
It is currently debated whether vitamin D requirements during pregnancy differ from those during non-gravid states. In current analyses, we aimed to determine the best model for the association between PTH and serum 25-hydroxyvitamin D (25(OH)D) and the threshold for circulating 25(OH)D at which serum parathyroid hormone (PTH) is suppressed. This multicenter prospective cross-sectional study was conducted on 227 Iranian pregnant women aged 15-45 years in their third trimester of pregnancy. The locally weighted smoothing scatter plot (LOWESS) was used to determine the curvilinear shape of the 25(OH)D/PTH relationship. Linear and non-linear methods were employed to determine the best fit and cut-point for serum 25(OH)D concentration. The median serum 25(OH)D and corresponding serum PTH concentration were 17⋅26 (13⋅44-23⋅08) ng/ml and 19⋅46 (15⋅08-25⋅04) pg/ml in our study population, respectively. The LOWESS curve suggested a non-linear and monotonic with a negative slope relation between PTH (pg/ml) and serum 25(OH)D (ng/ml). The optimal model for the association between PTH and serum 25(OH)D was a one-term fractional polynomial (FP1) (AIC = 1640⋅463). The FP1 analysis identified the 25(OH)D threshold of 12⋅48 ng/ml at which serum PTH rapidly rose. The expected degree of PTH stimulation seems to have a linear trend as 25(OH)D falls below 40 ng/ml. 25(OH)D (ng/ml) and PTH (pg/ml) had a non-linear and monotonic relationship with a negative slope. Our data suggest that a 25(OH)D threshold of 12⋅48 ng/ml is sufficient for parathyroid hormone suppression, which could be used to screen for deficient individuals.
Topics: Female; Humans; Pregnancy; Calcifediol; Cross-Sectional Studies; Iran; Parathyroid Hormone; Prospective Studies; Adolescent; Young Adult; Adult; Middle Aged
PubMed: 36721726
DOI: 10.1017/jns.2022.110 -
International Journal of Environmental... Dec 2021: The aim of this study was to assess the relationship between serum 25-hydroxyvitamin D [25(OH)D] and serum intact parathyroid hormone (PTH) in Chinese childbearing...
: The aim of this study was to assess the relationship between serum 25-hydroxyvitamin D [25(OH)D] and serum intact parathyroid hormone (PTH) in Chinese childbearing women, and to estimate the optimum threshold of 25(OH)D that maximally inhibits the PTH, which is considered to be the optimal status for vitamin D sufficiency. : Serum samples were selected from the biological samples' bank of the Chinese Chronic Diseases and Nutrition Survey (CCDNS) 2015. The serum 25(OH)D concentration was determined by liquid chromatography tandem mass spectrometry and the serum PTH was determined by electronic chemiluminescence. Simple linear and partial correlation analysis, locally weighted regression smooth scatterplot (LOESS), nonlinear least squares estimation (NLS), and segmented regression (SR) were utilized to estimate the relationship of 25(OH)D and PTH, and to determine the threshold of 25(OH)D. Results: A total of 1568 serum samples of 25(OH)D concentration and PTH concentration were analyzed. A significant inverse relationship between 25(OH)D and PTH concentration was observed below 15.25 (14.22-16.28) ng/mL, and PTH decreased slowly with the increase of 25(OH)D above 16.75 (15.43-18.06) ng/mL after adjusting by age, latitude, city type, season, corrected calcium, and phosphorus. A very short plateau of PTH was found at 15.25 ng/mL and 16.75 ng/mL in terms of 25(OH)D according to LOESS, NLS, and SR. : The serum 25(OH)D was negatively correlated with the serum PTH. The threshold of VitD sufficiency was found in the range of 14.22-18.06 ng/mL in terms of serum 25(OH)D concentration for Chinese childbearing women aged 18-44 years old.
Topics: Adolescent; Adult; China; Female; Humans; Parathyroid Hormone; Vitamin D; Vitamin D Deficiency; Vitamins; Young Adult
PubMed: 34948669
DOI: 10.3390/ijerph182413060 -
BMC Musculoskeletal Disorders Jan 2022Parathyroid hormone, with its anabolic effect on bone formation, has shown excellent outcomes of curing postmenopausal osteoporosis as well as enhancing osseointegration...
Parathyroid hormone enhances gap healing and osseointegration in orthopedic porous coated titanium implants: a correlative micro-computed tomographic, histomorphometric and biomechanical analysis.
BACKGROUND
Parathyroid hormone, with its anabolic effect on bone formation, has shown excellent outcomes of curing postmenopausal osteoporosis as well as enhancing osseointegration around orthopaedic and stomatologic implants.The purpose of the present study is to test if low-dose intermittent PTH (1-34) treatment could achieve a satisfactory osseointegration in 2-mm peri-implant gaps, as to provide a new idea for improving the stability of such prosthesis, which will be of great clinical value.
METHODS
A custom-made titanium implant was implanted on the calvarium of New Zealand White rabbits. 48 male rabbits were randomly divided into control and PTH group. PTH group received subcutaneous injection of PTH (20 μg/day, 5 days/week). Animals were sacrificed at 4 and 8 weeks after surgery. Quantitative micro-computed tomography, histology and biomechanical pull-out testing were performed to evaluate the gap healing at implantation site.
RESULTS
Analysis of micro-computed tomography demonstrated that PTH group achieved more new bone formation in 2-mm gaps and on bone-implant interface. Quantitatively, significant differences were observed between two groups in regard to BIC and BV/TV at each time-point. Histological staining revealed that PTH group had a superiority in trabecular number, thickness, separation and better osseointegration compared to control group. As for biomechanical pull-out testing, PTH group also showed significant improvement of ultimate force than control group.
CONCLUSIONS
Low-dose intermittent administration of PTH for 4 and 8 weeks enhances early osseointegration and fixation of orthopedic implants surrounded by a 2-mm gap in terms of increased bone regeneration and mechanical stability. These findings suggest PTH a potential for reducing the postoperative complications of implants by improving bone healing at peri-implant gaps.
Topics: Animals; Male; Orthopedics; Osseointegration; Parathyroid Hormone; Porosity; Prostheses and Implants; Rabbits; Titanium; X-Ray Microtomography
PubMed: 34980060
DOI: 10.1186/s12891-021-04917-y