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FEBS Letters Apr 2023The parathyroid hormone (PTH) regulates the calcium and phosphate level in blood after secretion from parathyroid chief cells. The pre- and pro-sequences of precursor...
The parathyroid hormone (PTH) regulates the calcium and phosphate level in blood after secretion from parathyroid chief cells. The pre- and pro-sequences of precursor preproPTH get cleaved during PTH maturation. In secretory granules, PTH forms functional amyloids. Using thioflavin T fibrillation assays, circular dichroism, NMR spectroscopy, and cellular cAMP activation, we show that the pro-sequence prevents premature fibrillation by impairing primary nucleation because of Coulomb repulsion of positively charged residues. Under seeding or high salt conditions or in the presence of heparin at pH 5.5, proPTH fibril formation is delayed, but the monomer release properties are conserved. ProPTH can still activate in cellulo PTH receptor 1 but with impaired potency. These findings give some perspectives on medical applications of PTH in hormone therapy.
Topics: Amyloid; Protein Precursors; Parathyroid Hormone; Parathyroid Glands; Calcium
PubMed: 36700832
DOI: 10.1002/1873-3468.14587 -
Die Pharmazie Aug 2016Bone diseases such as osteoporosis, osteoarthritis, bone tumours and bone fractures are rather common and not just in the elderly. Parathyroid hormone (PTH) is... (Review)
Review
Bone diseases such as osteoporosis, osteoarthritis, bone tumours and bone fractures are rather common and not just in the elderly. Parathyroid hormone (PTH) is responsible for maintaining calcium homeostasis, increasing bone mineral density (BMD), increasing cortical and trabecular bone thickness and thus increasing bone strength. Teriparatide (PTH 1-34) has the same effects as endogenous PTH and is pharmacologically used to treat bone diseases such as osteoporosis, osteoarthritis, bone fractures and bone tumours. This review discusses how PTH 1-34 plays a role in managing bone diseases. Clinical studies have shown that short or intermittent dosing of PTH 1-34 has minimal adverse effects, while long-term dosing (over two years) has been linked to de novo osteoarthritis and bone deformation. Currently PTH therapy is only approved in the treatment of post-menopausal osteoporosis, however it is also proven to have effects in treating osteoarthritis, bone tumours and bone fractures. If the patient undergoing therapy is closely monitored, the major pitfalls are very unlikely to take place, thus it is highly recommended that patients be closely monitored by a medical practitioner.
Topics: Aged; Bone Density Conservation Agents; Bone Diseases; Diphosphonates; Humans; Parathyroid Hormone; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 29442028
DOI: 10.1691/ph.2016.6008 -
Journal of Translational Medicine Nov 2023Non-union formation still represents a major burden in trauma and orthopedic surgery. Moreover, aged patients are at an increased risk for bone healing failure....
BACKGROUND
Non-union formation still represents a major burden in trauma and orthopedic surgery. Moreover, aged patients are at an increased risk for bone healing failure. Parathyroid hormone (PTH) has been shown to accelerate fracture healing in young adult animals. However, there is no information whether PTH also stimulates bone regeneration in atrophic non-unions in the aged. Therefore, the aim of the present study was to analyze the effect of PTH on bone regeneration in an atrophic non-union model in aged CD-1 mice.
METHODS
After creation of a 1.8 mm segmental defect, mice femora were stabilized by pin-clip fixation. The animals were treated daily with either 200 mg/kg body weight PTH 1-34 (n = 17) or saline (control; n = 17) subcutaneously. Bone regeneration was analyzed by means of X-ray, biomechanics, micro-computed tomography (µCT) imaging as well as histological, immunohistochemical and Western blot analyses.
RESULTS
In PTH-treated animals bone formation was markedly improved when compared to controls. This was associated with an increased bending stiffness as well as a higher number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and CD31-positive microvessels within the callus tissue. Furthermore, PTH-treated aged animals showed a decreased inflammatory response, characterized by a lower number of MPO-positive granulocytes and CD68-positive macrophages within the bone defects when compared to controls. Additional Western blot analyses demonstrated a significantly higher expression of cyclooxygenase (COX)-2 and phosphoinositide 3-kinase (PI3K) in PTH-treated mice.
CONCLUSION
Taken together, these findings indicate that PTH is an effective pharmacological compound for the treatment of non-union formation in aged animals.
Topics: Humans; Mice; Animals; Aged; X-Ray Microtomography; Phosphatidylinositol 3-Kinases; Bone Regeneration; Parathyroid Hormone; Fracture Healing
PubMed: 37996876
DOI: 10.1186/s12967-023-04661-y -
Recent Progress in Hormone Research 1989Many factors, such as interleukin 1, TGF alpha, tumor necrosis factor alpha and beta, and PGs, have been implicated in etiological roles in HHM (Martin and Mundy, 1987).... (Review)
Review
Many factors, such as interleukin 1, TGF alpha, tumor necrosis factor alpha and beta, and PGs, have been implicated in etiological roles in HHM (Martin and Mundy, 1987). Much interest in the past has also centered upon the likelihood of ectopic secretion of PTH in this condition. We have purified a protein (PTHrP) implicated in HHM from a human lung cancer cell line (BEN). Full-length cDNA clones have been isolated and were found to encode a prepropeptide of 36 amino acids and a mature protein of 141 amino acids. Eight of the first 13 amino acids were identical with human PTH, although antisera directed to the NH2 terminus of PTHrP do not recognize PTH; this homology is not maintained in the remainder of the molecule. PTHrP therefore represents a previously unrecognized hormone, possibly related to the PTH gene by a gene duplication mechanism. In support of this notion, the PTHrP gene has been localized to the short arm of chromosome 12; it is believed that chromosome 11, containing the PTH gene, and chromosome 12 are evolutionarily related. In addition, the human PTHrP gene has been isolated, characterized, and shown to have a similar intron--exon organization as the PTH gene. It is possible that the original ancestral gene is indeed the PTHrP gene; resolution of this question awaits studies in lower species. Peptides synthesized to the predicted protein sequence have enabled detailed structure-function studies that have identified NH 2-terminal sequences to be responsible for the biological effects of the molecule. Antibodies raised against the various synthetic peptides have led to the immunohistochemical localization of PTHrP in many human squamous cell carcinomas as well as in a subpopulation of keratinocytes of normal skin. The availability of these antibodies has opened the way for the development of a radioimmunoassay to detect PTHrP in the sera of cancer patients at risk of developing hypercalcemia. The recent characterization of PTHrP-like activity in the ovine fetus suggests some physiological function for PTHrP. It is possible that PTHrP, as the fetal counterpart of PTH, has the role of maintaining the maternal-fetal calcium gradient. The isolation and characterization of PTHrP have added to our understanding of the mechanisms of hypercalcemia and may contribute to the understanding of other metabolic bone diseases, such as osteoporosis and Paget's disease. Finally, and perhaps most importantly, PTHrP may play a hitherto unrecognized role in normal cell physiology.
Topics: Amino Acid Sequence; Animals; Base Sequence; Cloning, Molecular; DNA; Humans; Hypercalcemia; Molecular Sequence Data; Parathyroid Hormone
PubMed: 2682846
DOI: 10.1016/b978-0-12-571145-6.50014-5 -
Journal of Bone and Mineral Research :... Nov 2002Biologically active parathyroid hormone (PTH) in humans with normal renal function circulates predominantly as an 84 amino acid peptide. PTH fragments of varying length... (Review)
Review
Biologically active parathyroid hormone (PTH) in humans with normal renal function circulates predominantly as an 84 amino acid peptide. PTH fragments of varying length arise either from metabolism of the intact hormone within the parathyroid glands or in peripheral tissues, such as liver, and the resulting carboxyl-terminal peptides are eliminated mainly by glomerular filtration and subsequent tubular degradation. Most of the initially raised anti-PTH antisera were directed against epitopes within the mid- or carboxyl-terminal regions of the hormone. These antibodies were used for the development of conventional, displacement-type radioimmunoassays, but provided only an index of the biologically active PTH(1-84) in the circulation. Subsequently developed immunometric assays use two distinct antibodies, a capture antibody usually directed against a carboxyl-terminal portion of PTH(1-84) and a radio- or enzyme-labeled detection antibody usually directed against the amino-terminal portion of the hormone. Such assays were thought to detect largely, if not exclusively, intact PTH, thus providing the concentration of biologically active hormone in blood, which is especially important for establishing the diagnosis of hyperparathyroidism. However, serum samples from normal subjects and patients with primary or secondary hyperparathyroidism have demonstrated that most immunometric two-site sandwich assays detect, besides PTH(1-84), one or more recently discovered large carboxyl-terminal PTH fragments that lack a portion of the amino-terminal end of the molecule. Some of these amino-terminally truncated PTH molecules [ntPTH(1-84)] exhibit an elution profile on high performance liquid chromatography (HPLC) that is indistinguishable from that of synthetic PTH(784). Such peptides were previously thought to be of minimal if any biological activity, but recent studies have shown that synthetic PTH(7-84) has hypocalcemic properties in vivo and that it inhibits osteoclastic bone resorption and the formation of mature osteoclasts in vitro. It is currently unclear whether important differences in disease states can be revealed by comparing results obtained with older immunometric assays that measure the full-length hormone and ntPTH(1-84) versus newer assays that measure only PTH(1-84). Therefore, whereas most immunometric PTH assay systems are appropriate for the diagnosis of primary hyperparathyroidism, it is possible that immunometric assays designed to detect only PTH(1-84) will be more useful in certain diagnostic studies, for intraoperative PTH monitoring and for assessing the pulsatility of PTH secretion. In addition, the ability to distinguish between the relative concentrations of ntPTH(1-84) versus PTH(1-84) may reveal previously unsuspected roles for the ntPTH(1-84) fragments in the pathophysiology of patients with end-stage renal disease and/or other disorders involving parathyroid hormone.
Topics: Chromatography, High Pressure Liquid; Epitopes; Humans; Hyperparathyroidism; Immune Sera; Immunoassay; Parathyroid Hormone; Peptide Fragments; Reference Values
PubMed: 12412782
DOI: No ID Found -
Clinics in Laboratory Medicine Mar 2004There has been a clear progression in assays for the analysis of PTH and its clinical applications. This includes the innovative use of PTH as a point-of-care assay as... (Review)
Review
There has been a clear progression in assays for the analysis of PTH and its clinical applications. This includes the innovative use of PTH as a point-of-care assay as an intraoperative measure of the success of parathyroid surgery. The rapid PTH assay has served as a model for the development of other rapid hormone assays, such as for adrenocorticotropic hormone,although the clinical usefulness of these other applications is less well established. Knowledge of the circulating forms of PTH continues to progress. Information about the biologic and immunologic activities of these forms will aid in the interpretation and clinical use of current assays and in the development of new assays with improved specificities. The clinical laboratory will continue to play a vital role in providing testing and support for this important mediator of mineral metabolism.
Topics: Biomarkers; Chemistry, Clinical; Humans; Monitoring, Intraoperative; Parathyroid Diseases; Parathyroid Hormone
PubMed: 15157563
DOI: 10.1016/j.cll.2004.01.005 -
The Annals of Pharmacotherapy Sep 2005To present the chemistry, pharmacology, and pharmacokinetics of parathyroid hormone (PTH) (1-84) and review the available clinical trials that evaluate its efficacy and... (Review)
Review
OBJECTIVE
To present the chemistry, pharmacology, and pharmacokinetics of parathyroid hormone (PTH) (1-84) and review the available clinical trials that evaluate its efficacy and safety; clinical applicability of this agent and its relationship to other Food and Drug Administration (FDA)-approved medications for treatment of osteoporosis are also discussed.
DATA SOURCES
A MEDLINE search (1996-December 2004) was completed, along with a review of information obtained from the manufacturer, NPS Pharmaceuticals. Key search terms included parathyroid hormone, PTH (1-84), and ALX 111.
STUDY SELECTION AND DATA EXTRACTION
Studies were selected based on their relevance and availability. Pertinent information, including objectives, design, demographics, outcomes, adverse events, dosing strategies, and therapeutic controversies, was extracted.
DATA SYNTHESIS
PTH (1-84) is being developed for treatment of osteoporosis. Recent studies have shown that, when administered intermittently as a subcutaneous injection, PTH (1-84) produces an increase in bone mineral density and prevents vertebral fractures. The fact that this agent contains the C-terminal region of PTH may differentiate it from PTH (1-34), teriparatide, which is approved by the FDA for treatment of osteoporosis. Further trials are necessary to determine the role of PTH (1-84) in combination with other treatments for osteoporosis and/or the order in which PTH (1-84) is given with these other agents. There are currently no comparative trials with other osteoporosis treatment modalities.
CONCLUSIONS
PTH (1-84), when given intermittently as a subcutaneous injection, appears to be a safe and efficacious treatment option for osteoporosis. Further trials are needed to determine its specific place in therapy compared with other treatment options.
Topics: Aged; Child; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Humans; Osteoporosis; Parathyroid Hormone; Randomized Controlled Trials as Topic
PubMed: 16076911
DOI: 10.1345/aph.1G146 -
Joint Bone Spine May 2006Clinical data suggested that parathyroid hormone (PTH) might be effective in improving bone mass in patients with osteoporosis, providing its resorptive effects, which... (Review)
Review
Clinical data suggested that parathyroid hormone (PTH) might be effective in improving bone mass in patients with osteoporosis, providing its resorptive effects, which are particularly marked at cortical sites, were kept under control. We reviewed the evidence that intermittent PTH therapy is a valid treatment option whose predominant effect is bone anabolism. In cell culture studies, PTH affected both bone formation and bone resorption, suggesting that the net result of PTH therapy may be either bone gain or bone loss depending on the dosage, mode of administration, bone site, and animal species. Histological studies established that intermittent PTH therapy was associated with an increase in trabecular bone and, importantly, with improvements in trabecular and cortical microarchitectural parameters that have not been reported with antiresorptive drugs. This anabolic effect of intermittent PTH therapy translates into increased biomechanical strength, despite the increase in endocortical porosity seen in humans and nonhuman primates. The biochemical response profile to intermittent PTH therapy in clinical trials indicated a phase of isolated anabolism followed by an overall increase in bone remodeling that predominantly affected bone formation, the result being a large increase in spinal bone mineral density as early as the first treatment year. Thus, intermittent PTH therapy exerts predominantly anabolic effects on bone.
Topics: Animals; Bone Density; Bone Resorption; Bone and Bones; Cells, Cultured; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Osteogenesis; Osteoporosis; Parathyroid Hormone; Tomography, X-Ray Computed
PubMed: 16563840
DOI: 10.1016/j.jbspin.2005.11.007 -
Advances in Experimental Medicine and... 1986
Review
Topics: Animals; Hormone Antagonists; Humans; Parathyroid Hormone; Structure-Activity Relationship
PubMed: 3551538
DOI: 10.1007/978-1-4684-5206-8_40 -
The New England Journal of Medicine Nov 1979
Review
Topics: Adenoma; Animals; Bone and Bones; Cattle; Dogs; Humans; Hyperparathyroidism; Kidney; Liver; Molecular Weight; Parathyroid Hormone; Parathyroid Neoplasms; Radioimmunoassay; Rats
PubMed: 386126
DOI: 10.1056/NEJM197911153012005