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1
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Zhang D, Cai Y, Sun Y, Zeng P, Wang W, Wang W, Cai C. Adverse events reporting of Etelcalcetide: a real-word analysis from FAERS database. J Pharm Policy Pract 2025; 18:2479072. [PMID: 40170738 PMCID: PMC11960307 DOI: 10.1080/20523211.2025.2479072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2025] Open
Abstract
Background This study's main goal was to closely monitor and record adverse events (AEs) related to the medication Etelcalcetide, which is used to treat secondary hyperparathyroidism (SHPT, which is defined as elevated parathyroid hormone (PTH) levels in response to abnormalities in the calcium, phosphate, and vitamin D homeostasis). Optimising patient safety and offering evidence-based recommendations for the proper use of this medication are the ultimate goals. Methods A thorough collection and analysis of reports from the FDA Adverse Event Reporting System (FAERS) database was conducted, encompassing the first quarter of 2014 to the first quarter of 2024. Robust algorithms including as ROR, PRR, BCPNN, and EBGM were employed for proportional analysis, enabling efficient data mining to measure signals linked to AEs related to Etelcalcetide. Results Based on the reports gathered, the number of patients in the Etelcalcetide population was found to be 2,472 (5,435 AEs). As expected, the study's findings revealed the occurrence of Decreased blood calcium, Hypophosphatemia, among other AEs, which are in line with the instructions in the medication insert. Furthermore, unforeseen major AEs were noted at the preferred term (PT) level. These included hunt stenosis, Shunt aneurysm, Shunt occlusion, Shunt infection and Peripheral arterial occlusive disease (PAOD) and so on. These results point to the possibility of AEs that are not presently listed in the medication description. Conclusion This work successfully identified previously unidentified and novel signals linked to AEs associated with the administration of Etelcalcetide, offering crucial insights into the intricate relationship between AEs and Etelcalcetide use. In the context of Etelcalcetide therapy, the study's findings highlight the vital significance of diligent surveillance and ongoing monitoring for the prompt detection and efficient management of AEs and to enhance overall patient safety and well-being.
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Affiliation(s)
- Dongdong Zhang
- College of Otorhinolaryngology Head and Neck Surgy, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, People's Republic of China
| | - Ying Cai
- College of Otorhinolaryngology Head and Neck Surgy, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, People's Republic of China
| | - Yixin Sun
- College of Otorhinolaryngology Head and Neck Surgy, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, People's Republic of China
| | - Peiji Zeng
- College of Otorhinolaryngology Head and Neck Surgy, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, People's Republic of China
| | - Wei Wang
- College of Otorhinolaryngology Head and Neck Surgy, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, People's Republic of China
| | - Wenhui Wang
- College of Otorhinolaryngology Head and Neck Surgy, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, People's Republic of China
| | - Chengfu Cai
- College of Otorhinolaryngology Head and Neck Surgy, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, People's Republic of China
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Henner DE, Drambarean B, Gerbeling TM, Kendrick JB, Kendrick WT, Koester-Wiedemann L, Nickolas TL, Rastogi A, Rauf AA, Dyson B, Singer MC, Desai P, Fox KM, Cheng S, Goodman W. Practice patterns on the management of secondary hyperparathyroidism in the United States: Results from a modified Delphi panel. PLoS One 2025; 20:e0266281. [PMID: 39888902 PMCID: PMC11785329 DOI: 10.1371/journal.pone.0266281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 03/17/2022] [Indexed: 02/02/2025] Open
Abstract
BACKGROUND Secondary hyperparathyroidism (SHPT) is common in patients with chronic kidney disease (CKD). Many recommendations in the Kidney Disease Improving Global Outcomes (KDIGO) CKD-mineral and bone disorder guidelines are supported by modest evidence and predate the approval of newer agents. Therefore, an expert panel defined consensus SHPT practice patterns in the United States with real-world context from the nephrology community. METHODS Ten US healthcare providers and one patient participated in a modified Delphi method comprising three phases. Consensus was determined via iterative responses to a questionnaire based on the 2009 and 2017 KDIGO guidelines and published literature on the identification, evaluation, monitoring, and interventional strategies for patients with SHPT. The threshold for consensus was 66% agreement. RESULTS Panelists generally agreed with KDIGO recommendations, with some differences. Consensus was reached on 42/105 (40%), 95/105 (90.5%), and 105/105 (100%) questions after phases 1, 2, and 3, respectively. Panelists unanimously agreed that SHPT treatment is often started late. There was a preference for serum phosphate level <4.6 mg/dL, and consensus to maintain serum calcium levels <9.5 mg/dL. There was unanimous agreement for vitamin D analogues as first-line options in patients not on dialysis with severe, progressive SHPT and unanimous preference for intravenous calcimimetic, etelcalcetide, in appropriate in-center dialysis patients. Factors such as formularies, dialysis center protocols, and insurance were recognized to influence therapeutic strategies. CONCLUSIONS Expert consensus was reached on SHPT management, further defining therapeutic strategies and medication use and emphasizing need for treatment early. Despite evidence-based treatment preferences supported by clinical experience, factors other than scientific evidence influence decision making, particularly with medications.
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Affiliation(s)
- David E. Henner
- Division of Nephrology, Berkshire Medical Center, Pittsfield, MA, United States of America
| | - Beatrice Drambarean
- University of Illinois Hospital & Health Sciences System, Chicago, IL, United States of America
| | | | - Jessica B. Kendrick
- Division of Renal Diseases and Hypertension, University of Colorado, Aurora, CO, United States of America
| | | | - Lisa Koester-Wiedemann
- Division of Nephrology, Washington University School of Medicine, St Louis, MO, United States of America
| | - Thomas L. Nickolas
- Division of Nephrology, Columbia University Irving Medical Center, New York, NY, United States of America
| | - Anjay Rastogi
- Division of Nephrology, UCLA School of Medicine, Los Angeles, CA, United States of America
| | - Anis A. Rauf
- Nephrology Associates of Northern Illinois, Oakbrook, IL, United States of America
| | | | - Michael C. Singer
- Department of Otolaryngology–Head and Neck Surgery, Henry Ford Hospital, Detroit, MI, United States of America
| | - Pooja Desai
- Amgen, Inc., Thousand Oaks, CA, United States of America
| | | | - Sunfa Cheng
- Amgen, Inc., Thousand Oaks, CA, United States of America
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3
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Himmerkus N, Quintanova C, Bhullar H, van Megen WH, Deluque AL, Skjødt K, Bogdanovic M, Bleich M, Alexander RT, Dimke H. Calcium-Sensing Receptor in the Thick Ascending Limb and Renal Response to Hypercalcemia. J Am Soc Nephrol 2025:00001751-990000000-00534. [PMID: 39836479 DOI: 10.1681/asn.0000000612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 01/08/2025] [Indexed: 01/23/2025] Open
Abstract
Background:
The parathyroid calcium-sensing receptor (CASR) controls the release of parathyroid hormone (PTH) in response to changes in serum calcium levels. Activation of the renal CASR increases urinary calcium excretion and is particularly important when CASR-dependent reductions in PTH fail to lower serum calcium. However, the role of the renal CASR in protecting against hypercalcemia and the direct effects of chronic CASR activation on tubular calcium handling remains to be fully elucidated.
Methods:
Experimental hypercalcemia was induced using the Vitamin D analog (Dihydrotachysterol, DHT) in mice with Ksp-Cre dependent deletion of the Casr (Ksp-Casr) in kidney with Cre negative littermates (WT) serving as controls. Urinary and fecal electrolyte determinations, dual-energy x-ray absorptiometry, molecular and biochemical evaluation, and in vitro tubule microperfusion were performed in both sexes.
Results:
Ksp-Cre-driven Casr deletion strongly reduced CASR abundance in the thick ascending limb (TAL). At baseline, no marked differences were detected in electrolyte handling and tubular permeability characteristics across the TAL. 3 days of DHT administration induced hypercalcemia in both WT and Ksp-Casr mice. However, while WT mice developed hypercalciuria, this response was absent in Ksp-Casr mice. Urinary excretion of magnesium and other electrolytes did not differ between hypercalcemic WT and Ksp-Casr mice. Intestinal electrolyte absorption was comparable between the two groups. Microperfusion of isolated cortical TALs revealed no baseline differences in the transepithelial voltage, resistance, or ion permeabilities. Following hypercalcemia, transepithelial resistance increased and calcium permeability markedly decreased in WT mice, but not in Ksp-Casr mice, with only minor alterations in magnesium permeability and no changes in transepithelial voltage.
Conclusions:
In hypercalcemic mice, absence of the CASR in TAL prevented the increase in urinary calcium excretion. The CASR specifically regulated the paracellular permeability of the TAL, especially for calcium.
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Affiliation(s)
- Nina Himmerkus
- Institute of Physiology, Christian-Albrechts-University, Kiel, Germany
| | | | - Harneet Bhullar
- Membrane Protein Disease Research Group, The University of Alberta, Edmonton, Alberta, Canada
| | | | - Amanda Lima Deluque
- Membrane Protein Disease Research Group, The University of Alberta, Edmonton, Alberta, Canada
- Department of Pediatrics, The University of Alberta, Edmonton, Alberta, Canada
| | - Karsten Skjødt
- Department of Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Milos Bogdanovic
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Markus Bleich
- Institute of Physiology, Christian-Albrechts-University, Kiel, Germany
| | - R Todd Alexander
- Membrane Protein Disease Research Group, The University of Alberta, Edmonton, Alberta, Canada
- Department of Pediatrics, The University of Alberta, Edmonton, Alberta, Canada
| | - Henrik Dimke
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
- Department of Nephrology, Odense University Hospital, Odense, Denmark
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4
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Walker V. The Molecular Biology of Placental Transport of Calcium to the Human Foetus. Int J Mol Sci 2025; 26:383. [PMID: 39796238 PMCID: PMC11720126 DOI: 10.3390/ijms26010383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
From fertilisation to delivery, calcium must be transported into and within the foetoplacental unit for intracellular signalling. This requires very rapid, precisely located Ca2+ transfers. In addition, from around the eighth week of gestation, increasing amounts of calcium must be routed directly from maternal blood to the foetus for bone mineralisation through a flow-through system, which does not impact the intracellular Ca2+ concentration. These different processes are mediated by numerous membrane-sited Ca2+ channels, transporters, and exchangers. Understanding the mechanisms is essential to direct interventions to optimise foetal development and postnatal bone health and to protect the mother and foetus from pre-eclampsia. Ethical issues limit the availability of human foetal tissue for study. Our insight into the processes of placental Ca2+ handling is advancing rapidly, enabled by developing genetic, analytical, and computer technology. Because of their diverse sources, the reports of new findings are scattered. This review aims to pull the data together and to highlight areas of uncertainty. Areas needing clarification include trafficking, membrane expression, and recycling of channels and transporters in the placental microvilli; placental metabolism of vitamin D in gestational diabetes and pre-eclampsia; and the vascular effects of increased endothelial Orai expression by pregnancy-specific beta-1-glycoproteins PSG1 and PSG9.
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Affiliation(s)
- Valerie Walker
- Department of Clinical Biochemistry, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton SO16 6YD, UK
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5
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Nanoff C, Yang Q, Hellinger R, Hermann M. Activation of the Calcium-Sensing Receptor by a Subfraction of Amino Acids Contained in Thyroid Drainage Fluid. ACS Pharmacol Transl Sci 2024; 7:1937-1950. [PMID: 39022353 PMCID: PMC11249632 DOI: 10.1021/acsptsci.3c00350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 06/03/2024] [Accepted: 06/17/2024] [Indexed: 07/20/2024]
Abstract
Hypoparathyroidism is a common sequela of thyroid surgery; in this study, we aimed at exploring the pathogenesis behind it. The following premises suggest that wound fluid might be a causative agent. (i) Parathyroid hormone secretion is under feedback control by the calcium-sensing receptor, which responds to a diverse array of activating ligands. (ii) Postoperative hypoparathyroidism arises from a secretory deficiency of the parathyroid glands. Even in patients later unaffected by hypoparathyroidism, parathyroid hormone levels drop within hours after surgery. (iii) Wound fluid is bound to enter the tissue around the thyroid bed, where the parathyroid glands are located. Its composition is shaped by a series of proteolytic reactions triggered by wounding. Using thyroid drainage as a surrogate, we addressed the possibility that wound fluid contains compounds activating the calcium-sensing receptor. Drainage fluid ultrafiltrate was found to be rich in amino acids, and on separation by HPLC, compounds activating the calcium-sensing receptor partitioned with hydrophilic matter that rendered buffer acidic. The data show that glutamate and aspartate at millimolar concentrations supported activation of the calcium-sensing receptor, an effect contingent on low pH. In the presence of glutamate/aspartate, protons activated the calcium-sensing receptor with a pH50 of 6.1, and at pH 5, produced maximal activation. This synergistic mode of action was exclusive; glutamine/asparagine did not substitute for the acidic amino acids, nor did Ca2+ substitute for protons. NPS-2143, a negative allosteric receptor modulator completely blocked receptor activation by glutamate/aspartate and by fractionated drainage fluid. Thus, wound fluid may be involved in suppressing parathyroid hormone secretion.
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Affiliation(s)
- Christian Nanoff
- Centre
for Physiology and Pharmacology, Gaston H. Glock Laboratories for
Exploratory Drug Research, Medizinische
Universität Wien, Währinger Straße 13A, Vienna 1090, Austria
| | - Qiong Yang
- Centre
for Physiology and Pharmacology, Gaston H. Glock Laboratories for
Exploratory Drug Research, Medizinische
Universität Wien, Währinger Straße 13A, Vienna 1090, Austria
| | - Roland Hellinger
- Centre
for Physiology and Pharmacology, Gaston H. Glock Laboratories for
Exploratory Drug Research, Medizinische
Universität Wien, Währinger Straße 13A, Vienna 1090, Austria
| | - Michael Hermann
- Department
of Surgery, Vienna Hospital Association,
Klinik Landstraße, Juchgasse 25, Vienna 1030, Austria
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6
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Dimke H. New insights into renal calcium-sensing receptor activation. Curr Opin Nephrol Hypertens 2024; 33:433-440. [PMID: 38690798 DOI: 10.1097/mnh.0000000000000998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
PURPOSE OF REVIEW Activation of the calcium-sensing receptor (CASR) in the parathyroid gland suppresses the release of parathyroid hormone (PTH). Furthermore, activation of the renal CASR directly increases the urinary excretion of calcium, by inhibiting transepithelial calcium transport in the nephron. Gain-of-function mutations in the CASR gene lead to autosomal dominant hypocalcemia 1 (ADH1), with inappropriately low PTH levels and hypocalcemia, indicative of excessive activation of the parathyroid CASR. However, hypercalciuria is not always observed. The reason why the manifestation of hypercalciuria is not uniform among ADH1 patients is not well understood. RECENT FINDINGS Direct activation of the CASR in the kidney has been cumbersome to study, and an indirect measure to effectively estimate the degree of CASR activation following chronic hypercalcemia or genetic gain-of-function CASR activation has been lacking. Studies have shown that expression of the pore-blocking claudin-14 is strongly stimulated by the CASR in a dose-dependent manner. This stimulatory effect is abolished after renal Casr ablation in hypercalcemic mice, suggesting that claudin-14 abundance may gauge renal CASR activation. Using this marker has led to unexpected discoveries regarding renal CASR activation. SUMMARY These new studies have informed on renal CASR activation thresholds and the downstream CASR-regulated calcium transport mechanisms.
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Affiliation(s)
- Henrik Dimke
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark
- Department of Nephrology, Odense University Hospital, Odense, Denmark
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7
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Qian Z, Luo K, Zhang M, Yao G. Comparative analysis of calcium-sensing receptor (CaSR) expression and function in normal and abnormal human sperm and spermatogenic cells. ZYGOTE 2024; 32:250-255. [PMID: 39291604 DOI: 10.1017/s0967199424000091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The calcium-sensing receptor (CaSR) is a critical mediator of calcium homeostasis in various tissues. Its role in human reproduction, especially in sperm function and male fertility, remains not fully elucidated. This study investigates the expression patterns of CaSR in normal and abnormal sperm and spermatogenic cells and evaluates its potential effect on sperm motility and morphology. Using immunohistochemistry (IHC), quantitative PCR (qPCR), we assessed the expression levels of CaSR in normal sperm, spermatogonia, and cases of asthenozoospermia, oligozoospermia, and teratozoospermia. In vitro functional assays were performed to analyze the effects of CaSR modulation on sperm motility under varying conditions, including the presence of specific CaSR agonists and antagonists. Our study revealed distinct patterns of CaSR expression in normal sperm and spermatogonia compared with those in abnormal sperm samples, particularly in cases of asthenozoospermia, oligozoospermia, and teratozoospermia. A marked decrease in CaSR expression was evident in these abnormal samples, highlighting its significance in normal sperm functionality. Functional assays further elucidated the role of CaSR in sperm motility. Activation of CaSR through specific agonists enhanced sperm motility, while inhibition by antagonists led to reduced motility. Our findings suggest that CaSR plays a significant role in maintaining sperm functionality and that changes in its expression may be associated with male infertility. These insights into the molecular underpinnings of sperm physiology highlight CaSR as a potential therapeutic target for treating certain forms of male infertility.
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Affiliation(s)
- Zhengli Qian
- Department of Reproductive Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Zunyi Medical University,Zunyi, China
| | - Keyan Luo
- Department of Reproductive Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Zunyi Medical University,Zunyi, China
| | - Mingzhe Zhang
- Department of Reproductive Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Zunyi Medical University,Zunyi, China
| | - Guanping Yao
- Department of Reproductive Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Zunyi Medical University,Zunyi, China
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8
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Saglia C, Arruga F, Scolari C, Kalantari S, Albanese S, Bracciamà V, Corso Faini A, Brach Del Prever G, Luca M, Romeo C, Mioli F, Migliorero M, Tessaris D, Carli D, Amoroso A, Vaisitti T, De Sanctis L, Deaglio S. Functional evaluation of a novel nonsense variant of the calcium-sensing receptor gene leading to hypocalcemia. Eur J Endocrinol 2024; 190:296-306. [PMID: 38561929 DOI: 10.1093/ejendo/lvae035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 03/06/2024] [Accepted: 03/08/2024] [Indexed: 04/04/2024]
Abstract
OBJECTIVE The calcium-sensing receptor (CASR) gene encodes a G protein-coupled receptor crucial for calcium homeostasis. Gain-of-function CASR variants result in hypocalcemia, while loss-of-function variants lead to hypercalcemia. This study aims to assess the functional consequences of the novel nonsense CASR variant [c.2897_2898insCTGA, p.(Gln967*) (Q967*)] identified in adolescent patient with chronic hypocalcemia, a phenotype expected for a gain-of-function variants. DESIGN AND METHODS To functionally characterize the Q967* mutant receptor, both wild-type (WT) and mutant CASR were transiently transfected into HEK293T cells and calcium-sensing receptor (CaSR) protein expression and functions were comparatively evaluated using multiple read-outs. RESULTS Western blot analysis revealed that the CaSR mutant protein displayed a lower molecular weight compared with the WT, consistent with the loss of the last 122 amino acids in the intracellular domain. Mitogen-activated protein kinase activation and serum responsive element luciferase assays demonstrated that the mutant receptor had higher baseline activity than the WT. Extracellular-signal-regulated kinase/c-Jun N-terminal kinase phosphorylation, however, remained consistently high in the mutant, without significant modulations following exposure to increasing extracellular calcium (Ca2+o) levels, suggesting that the mutant receptor is more sensitive to Ca2+o compared with the WT. CONCLUSIONS This study provides functional validation of the pathogenicity of a novel nonsense CASR variant, resulting in an abnormally hyperfunctioning protein consistent with the patient's phenotype. Functional analyses indicate that mutant receptor is constitutively active and poorly sensitive to increasing concentrations of extracellular calcium, suggesting that the cytoplasmic tail may contain elements regulating signal transduction.
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Affiliation(s)
- Claudia Saglia
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Francesca Arruga
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Caterina Scolari
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Silvia Kalantari
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Serena Albanese
- Department of Public Health and Pediatric Sciences, University of Torino, Torino 10126, Italy
- Pediatric Endocrinology, Regina Margherita Childrens' Hospital, Torino 10126, Italy
| | - Valeria Bracciamà
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Angelo Corso Faini
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Giulia Brach Del Prever
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Maria Luca
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Carmelo Romeo
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Fiorenza Mioli
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | | | - Daniele Tessaris
- Department of Public Health and Pediatric Sciences, University of Torino, Torino 10126, Italy
- Pediatric Endocrinology, Regina Margherita Childrens' Hospital, Torino 10126, Italy
| | - Diana Carli
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Antonio Amoroso
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Tiziana Vaisitti
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
| | - Luisa De Sanctis
- Department of Public Health and Pediatric Sciences, University of Torino, Torino 10126, Italy
- Pediatric Endocrinology, Regina Margherita Childrens' Hospital, Torino 10126, Italy
| | - Silvia Deaglio
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
- Immunogenetics and Transplant Biology Unit, Città della Salute e della Scienza Hospital, Turin 10126, Italy
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9
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Tridimas A, Padidela R, Bassett J, Wood R, Lawson M, Fagbemi A, Morris TJ. Reducing Metabolic Bone Disease Burden in Intestinal Failure Children on Home Parenteral Nutrition. JPGN REPORTS 2023; 4:e368. [PMID: 38034429 PMCID: PMC10684215 DOI: 10.1097/pg9.0000000000000368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 12/02/2023]
Abstract
Objective To determine the prevalence of secondary hyperparathyroidism in a cohort of pediatric patients receiving home parenteral nutrition. Methods For a service review, a population-based cohort of 37 pediatric intestinal failure patients receiving long-term parenteral nutrition that underwent serial biochemical monitoring during a study period of approximately 4 years were examined. Following the production of an algorithm, a follow-up audit was carried out (n = 33) after approximately 6 months. Results Of the 37 patients examined in the initial service review, 22 (59%) were found to have an elevated parathyroid hormone (PTH) during the period of monitoring and 5 (14%) had a persistently elevated PTH. In the follow-up audit following the implementation of an algorithm, the number with elevated PTH reduced to 6 (18%) and no patients had persistently high levels. Conclusion Elevated PTH is a common biochemical finding in pediatric intestinal failure patients receiving home parenteral nutrition and its presence should alert clinicians to the need to optimize nutritional parameters such as calcium to phosphate molar ratio and vitamin D status; failure to do so may increase the future burden of metabolic bone disease in such patients. We propose that an algorithm may help in this endeavor.
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Affiliation(s)
- Andreas Tridimas
- From the Directorate of Clinical Biochemistry, Manchester University NHS Foundation Trust, Manchester, UK
- Clinical Biochemistry Department, Countess of Chester Hospital, Chester, UK
| | - Raja Padidela
- Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK
- Faculty of Biology Medicine and Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, UK
| | - John Bassett
- From the Directorate of Clinical Biochemistry, Manchester University NHS Foundation Trust, Manchester, UK
| | - Rachel Wood
- Department of Therapy and Dietetics, Royal Manchester Children’s Hospital, Manchester, UK
| | - Maureen Lawson
- Department of Paediatric Gastroenterology, Royal Manchester Children’s Hospital, Manchester, UK
| | - Andrew Fagbemi
- Department of Paediatric Gastroenterology, Royal Manchester Children’s Hospital, Manchester, UK
| | - Timothy J. Morris
- From the Directorate of Clinical Biochemistry, Manchester University NHS Foundation Trust, Manchester, UK
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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10
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Valiente-Gabioud AA, Fabritius A, Griesbeck O. Probing the interstitial calcium compartment. J Physiol 2023; 601:4217-4226. [PMID: 36073135 DOI: 10.1113/jp279510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/30/2022] [Indexed: 11/08/2022] Open
Abstract
Calcium in interstitial fluids is a crucial ion pool for entry into cells through a plethora of calcium-permeable channels. It is also sensed actively by dedicated receptors. While the mechanisms of global calcium homeostasis and regulation in body fluids appear well understood, more efforts and new technology are needed to elucidate local calcium handling in the small and relatively isolated interstitial spaces between cells. Here we review current methodology for monitoring interstitial calcium and highlight the potential of new approaches for its study. In particular, new generations of high-performance low-affinity genetically encoded calcium indicators could allow imaging of calcium in relatively inaccessible intercellular structures in live tissues and organisms.
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Affiliation(s)
- Ariel A Valiente-Gabioud
- Tools for Bio-Imaging, Max-Planck-Institute for Biological Intelligence (i.F.), Martinsried, Germany
| | - Arne Fabritius
- Tools for Bio-Imaging, Max-Planck-Institute for Biological Intelligence (i.F.), Martinsried, Germany
| | - Oliver Griesbeck
- Tools for Bio-Imaging, Max-Planck-Institute for Biological Intelligence (i.F.), Martinsried, Germany
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11
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Zhao Z, Yan Q, Li D, Li G, Cai J, Pan S, Duan J, Liu D, Liu Z. Relationship between serum iPTH and peritonitis episodes in patients undergoing continuous ambulatory peritoneal dialysis. Front Endocrinol (Lausanne) 2023; 14:1081543. [PMID: 37051200 PMCID: PMC10083419 DOI: 10.3389/fendo.2023.1081543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 03/01/2023] [Indexed: 03/29/2023] Open
Abstract
Background Peritonitis is considered as one of the most serious complications that cause hospitalization in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). There is limited evidence on the impact of the parathyroid hormone (PTH) on the first peritoneal dialysis (PD)-associated peritonitis episode. We aimed to investigate the influence of serum intact parathyroid hormone (iPTH) on peritonitis in patients undergoing PD. Methods This was a retrospective cohort study. Patients undergoing initial CAPD from a single center in China were enrolled. The baseline characteristics and clinical information were recorded. The primary outcome of interest was the occurrence of the first PD-associated peritonitis episode. Five Cox proportional hazard models were constructed in each group set. In group set 1, all participants were divided into three subgroups by tertiles of the serum concentration of iPTH; in group set 2, all participants were divided into three subgroups based on the serum concentration of iPTH with 150 pg/ml interval (<150, 150-300, and >300 pg/ml). Hazard ratios and 95% confidence intervals (CIs) were calculated for each model. The multivariate linear regression analysis elimination procedure assessed the association between the clinical characteristics at baseline and the iPTH levels. Restricted cubic spline models were constructed, and stratified analyses were also conducted. Results A total of 582 patients undergoing initial PD (40% women; mean age, 45.1 ± 11.5 years) from a single center in China were recruited. The median follow-up duration was 25.3 months. Multivariate Cox regression analysis showed that, in the fully adjusted model, a higher serum iPTH level (tertile 3, iPTH >300 pg/ml) was significantly associated with a higher risk of PD-associated peritonitis at 3 years [tertile 3: hazard ratio (HR) = 1.53, 95%CI = 1.03-2.55, p = 0.03; iPTH > 300 pg/ml: HR = 1.57, 95%CI = 1.08-2.27, p = 0.02]. The hazard ratio for every 100 pg/ml increase in serum iPTH level was 1.12 (95%CI = 1.05-1.20, p < 0.01) in the total cohort when treating iPTH as a continuous variable. Conclusions An elevated iPTH level was significantly associated with an increased risk of peritonitis in patients undergoing CAPD.
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Affiliation(s)
- Zihao Zhao
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Qianqian Yan
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
| | - Duopin Li
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
| | - Guangpu Li
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
| | - Jingjing Cai
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
| | - Shaokang Pan
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Jiayu Duan
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Dongwei Liu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhangsuo Liu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
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Athonvarangkul D, Wysolmerski JJ. Crosstalk within a brain-breast-bone axis regulates mineral and skeletal metabolism during lactation. Front Physiol 2023; 14:1121579. [PMID: 36875035 PMCID: PMC9979219 DOI: 10.3389/fphys.2023.1121579] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 01/27/2023] [Indexed: 02/18/2023] Open
Abstract
To support the increased calcium demands for milk production during lactation, a dramatic and reversible physiological response occurs to alter bone and mineral metabolism. This coordinated process involves a brain-breast-bone axis that integrates hormonal signals that allow for adequate calcium delivery to milk yet also protects the maternal skeletal from excessive bone loss or decreases in bone quality or function. Here, we review the current knowledge on the crosstalk between the hypothalamus, mammary gland, and skeleton during lactation. We discuss the rare entity of pregnancy and lactation associated osteoporosis and consider how the physiology of bone turnover in lactation may impact the pathophysiology of postmenopausal osteoporosis. Further understanding of the regulators of bone loss during lactation, particularly in humans, may provide insights into new therapies for osteoporosis and other diseases of excess bone loss.
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Affiliation(s)
- Diana Athonvarangkul
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
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Chandran M, Yeh LTL, de Jong MC, Bilezikian JP, Parameswaran R. Cognitive deficits in primary hyperparathyroidism - what we know and what we do not know: A narrative review. Rev Endocr Metab Disord 2022; 23:1079-1087. [PMID: 35994179 DOI: 10.1007/s11154-022-09750-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/04/2022] [Indexed: 10/15/2022]
Abstract
Classic symptoms of primary hyperparathyroidism (PHPT) are seen in approximately 20% of patients. While features such as kidney stones and skeletal disease are often highlighted as directly related to the disease, others can be even more prevalent. For example, cognitive dysfunction and reduced quality of life are common complaints in many patients, even among those who are classified as being asymptomatic. The pathophysiology of PHPT involves the impact of excess parathyroid hormone (PTH) on calcium metabolism. Referencing putative neurocognitive issues, many animal studies have illustrated the potential roles of PTH and PTH receptors in the brain. Functional imaging and pre-and post-parathyroidectomy studies have suggested a link between the neuronal impact of elevated PTH levels on specific functional aspects of the central nervous system, such as cognition. Confounding a direct role for PTH are hypercalcemia and vitamin D deficiency, both of which could conceivably alter CNS function in PHPT. The lack of strong evidence that parathyroidectomy improves cognition in patients with PHPT raises the question as to whether parathyroid surgery should be recommended on this basis alone. This narrative review summarizes the available literature on neurocognitive function in PHPT.
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Affiliation(s)
- Manju Chandran
- Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, Singapore, Singapore.
- DUKE-NUS Medical School, Singapore, Singapore.
| | - Lydia Tan Li Yeh
- Division of Endocrine Surgery, National University Health System, Singapore, Singapore
| | - Mechteld C de Jong
- Division of Endocrine Surgery, National University Health System, Singapore, Singapore
| | - John P Bilezikian
- Division of Endocrinology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA
| | - Rajeev Parameswaran
- Division of Endocrine Surgery, National University Health System, Singapore, Singapore
- Division of Endocrine Surgery, National University Hospital System, Singapore, Singapore
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Wherry TLT, Stabel JR. Bovine Immunity and Vitamin D 3: An Emerging Association in Johne's Disease. Microorganisms 2022; 10:1865. [PMID: 36144467 PMCID: PMC9500906 DOI: 10.3390/microorganisms10091865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/13/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
Mycobacterium avium subspecies paratuberculosis (MAP) is an environmentally hardy pathogen of ruminants that plagues the dairy industry. Hallmark clinical symptoms include granulomatous enteritis, watery diarrhea, and significant loss of body condition. Transition from subclinical to clinical infection is a dynamic process led by MAP which resides in host macrophages. Clinical stage disease is accompanied by dysfunctional immune responses and a reduction in circulating vitamin D3. The immunomodulatory role of vitamin D3 in infectious disease has been well established in humans, particularly in Mycobacterium tuberculosis infection. However, significant species differences exist between the immune system of humans and bovines, including effects induced by vitamin D3. This fact highlights the need for continued study of the relationship between vitamin D3 and bovine immunity, especially during different stages of paratuberculosis.
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Affiliation(s)
- Taylor L. T. Wherry
- Department of Veterinary Pathology, Iowa State University, Ames, IA 50011, USA
- Infectious Bacterial Diseases Research Unit, United States Department of Agriculture-Agricultural Research Service (USDA-ARS), National Animal Disease Center, Ames, IA 50010, USA
| | - Judith R. Stabel
- Infectious Bacterial Diseases Research Unit, United States Department of Agriculture-Agricultural Research Service (USDA-ARS), National Animal Disease Center, Ames, IA 50010, USA
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SALEPÇIOĞLU KAYA H, GÖNCÜ B, DÜZENLİ ÖF, YIĞMAN S, ERSOY YE, AKÇAKAYA A. Evaluation of Parathyroid allo-transplantation with the Presence of Auto-CASR Antibody. BEZMIALEM SCIENCE 2022. [DOI: 10.14235/bas.galenos.2021.6401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
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Bulska E, Gawor A, Konopka A, Wryk G, Czarkowska-Pączek B, Gajewski Z, Pączek L. Label-Free Mass Spectrometry-Based Quantitative Proteomics to Evaluate the Effects of the Calcium-Sensing Receptor Agonist Cinacalcet on Protein Expression in Rat Brains and Livers. MEDICAL SCIENCE MONITOR : INTERNATIONAL MEDICAL JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022; 28:e937338. [PMID: 35941808 PMCID: PMC9375513 DOI: 10.12659/msm.937338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Background Cinacalcet is a calcium-sensing receptor agonist that is clinically approved for the treatment of secondary hyperparathyroidism in chronic kidney disease and hypercalcemia in patients with parathyroid carcinoma. This study aimed to use quantitative mass spectrometry-based label-free proteomics to evaluate the effects of cinacalcet on protein expression in rat brains and livers. Material/Methods We randomly assigned 18 Wistar rats to 2 groups: an untreated control group (n=6) and a group treated with cinacalcet at a dose corresponding to the maximum dose used in humans (2 mg/kg/body weight, 5 days/week) divided into 7-day (n=6) and 21-day (n=6) treatment subgroups. A mass-spectrometry-based label-free quantitative proteomics approach using peptides peak area calculation was used to evaluate the changes in protein expression in examined tissues. Bioinformatics analysis of quantitative proteomics data was done using MaxQuant and Perseus environment. Results No changes in protein expression were revealed in the 7-day treatment subgroup. We detected 10 upregulated and 3 downregulated proteins in the liver and 1 upregulated protein in the brain in the 21-day treatment subgroup compared to the control group. Based on Gene Ontology classification, all identified differentially expressed proteins were indicated as molecular functions involved in the enzyme regulator activity (36%), binding (31%), and catalytic activity (19%). Conclusions These findings indicate that long-term cinacalcet therapy can impair phase II of enzymatic detoxication and can cause disturbances in blood hemostasis, lipid metabolism, and inflammatory mediators or contribute to the acceleration of cognitive dysfunction; therefore, appropriate patient monitoring should be considered.
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Affiliation(s)
- Ewa Bulska
- Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Warsaw, Poland
| | - Andrzej Gawor
- Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Warsaw, Poland
| | - Anna Konopka
- Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Warsaw, Poland
| | - Grzegorz Wryk
- Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Warsaw, Poland
| | | | - Zdzisław Gajewski
- Department of Large Animal Diseases and Clinic, Veterinary Research Center and Center for Biomedical Research, Institute of Veterinary Medicine, Warsaw University of Life Science, Warsaw, Poland
| | - Leszek Pączek
- Department of Immunology, Transplantology and Internal Disease, Medical University of Warsaw, Warsaw, Poland
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Abstract
Phagocytes play critical roles in the maintenance of organismal homeostasis and immunity. Central to their role is their ability to take up and process exogenous material via the related processes of phagocytosis and macropinocytosis. The mechanisms and functions underlying macropinocytosis have remained severely understudied relative to phagocytosis. In recent years, however, there has been a renaissance in macropinocytosis research. Phagocytes can engage in various forms of macropinocytosis including an "induced" form and a "constitutive" form. This chapter, however, will focus on constitutive macropinocytosis and its role in the maintenance of immunity. Functions previously attributed to macropinocytosis, including antigen presentation and immune surveillance, will be revisited in light of recent revelations and emerging concepts will be highlighted.
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Affiliation(s)
- Johnathan Canton
- Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada.
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van Megen WH, Tan RSG, Alexander RT, Dimke H. Differential parathyroid and kidney Ca 2+-sensing receptor activation in autosomal dominant hypocalcemia 1. EBioMedicine 2022; 78:103947. [PMID: 35313217 PMCID: PMC8935519 DOI: 10.1016/j.ebiom.2022.103947] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/11/2022] [Accepted: 03/03/2022] [Indexed: 12/04/2022] Open
Abstract
Background Parathyroid Ca2+-sensing receptor (CaSR) activation inhibits parathyroid hormone (PTH) release, while activation of renal CaSRs attenuates Ca2+ transport and increases expression of the pore-blocking claudin-14. Patients with autosomal dominant hypocalcemia 1 (ADH1), due to activating CASR mutations, exhibit hypocalcemia but not always hypercalciuria (elevated Ca2+ in urine). The latter promotes nephrocalcinosis and renal insufficiency. Although CaSRs throughout the body including the kidney harbor activating CASR mutations, it is not understood why only some ADH1 patients display hypercalciuria. Methods Activation of the CaSR was studied in mouse models and a ADH1 patient. In vitro CaSR activation was studied in HEK293 cells. Findings Cldn14 showed blood Ca2+ concentration-dependent regulation, which was absent in mice with kidney-specific Casr deletion, indicating Cldn14 is a suitable marker for chronic CaSR activation in the kidney. Mice with a gain-of-function mutation in the Casr (Nuf) were hypocalcemic with low plasma PTH levels. However, renal CaSRs were not activated at baseline but only after normalizing blood Ca2+ levels. Similarly, significant hypercalciuria was not observed in a ADH1 patient until blood Ca2+ was normalized. In vitro experiments indicate that increased CaSR expression in the parathyroid relative to the kidney could contribute to tissue-specific CaSR activation thresholds. Interpretation Our findings suggest that parathyroid CaSR overactivity can reduce plasma Ca2+ to levels insufficient to activate renal CaSRs, even when an activating mutation is present. These findings identify a conceptually new mechanism of CaSR-dependent Ca2+ balance regulation that aid in explaining the spectrum of hypercalciuria in ADH1 patients. Funding Erasmus+ 2018/E+/4458087, the Canadian Institutes for Health research, the Novo Nordisk Foundation, the Beckett Foundation, the Carlsberg Foundation and Independent Research Fund Denmark.
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Affiliation(s)
- Wouter H van Megen
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsløws Vej 21, 3rd floor, 5000 Odense C, Denmark; Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Rebecca Siu Ga Tan
- Membrane Protein Disease Research Group, Department of Physiology, University of Alberta, Edmonton, Canada; The Women's and Children's Health Research Institute, Edmonton, Alberta, Canada
| | - R Todd Alexander
- Membrane Protein Disease Research Group, Department of Physiology, University of Alberta, Edmonton, Canada; The Women's and Children's Health Research Institute, Edmonton, Alberta, Canada; Department of Pediatrics, 4-585 Edmonton Clinic Health Academy, University of Alberta, 11405 87th Avenue, Edmonton, Alberta T6G 2R7, Canada.
| | - Henrik Dimke
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsløws Vej 21, 3rd floor, 5000 Odense C, Denmark; Department of Nephrology, Odense University Hospital, Denmark.
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李 珮, 李 刚, 柳 丽, 黄 珊, 李 俊, 吴 唯. [Cultivation and characterization of primary human parathyroid cells from patients with severe secondary hyperparathyroidism]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:238-243. [PMID: 35365448 PMCID: PMC8983369 DOI: 10.12122/j.issn.1673-4254.2022.02.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Indexed: 06/14/2023]
Abstract
OBJECTIVE To establish an cell model of hyperparathyroidism by isolation, in vitro culture, and identification of parathyroid cells from patients with secondary hyperparathyroidism (SHPT). METHODS The parathyroid gland tissues obtained from 10 patients with SHPT were dissociated by collagenase digestion for primary culture of the parathyroid cells. Morphological changes and growth characteristics of the cells were assessed by microscopic imaging and cell counting. The mRNA and protein expression levels of parathyroid hormone (PTH), calcium-sensing receptor (CaSR), and glial cells missing 2 (GCM2) in the primary and passaged cells were determined by immunofluorescence, qRT-PCR, and Western blotting. RESULTS Primary cultures of parathyroid cells were successfully obtained. The cells exhibited a high expression of PTH shown by immunofluorescence assay and had a population doubling time of approximately 71.61 h. PTH secretion in the second-passage (P2) cells was significantly lower than that in the primary (P0) and first-passage (P1) cells (P < 0.001). Despite a significant downregulation of CaSR mRNA (P=0.017) and protein (P=0.006) in P1 cells as compared with P0 cells, no significant differences were found in mRNA and protein expressions of PTH or GCM2 between the two cell generations. CONCLUSION Primary cultures of parathyroid cells isolated from SHPT patients by collagenase digestion show similar biological properties to the cells in vivo.
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Affiliation(s)
- 珮婷 李
- />中南大学湘雅三医院乳甲外科，湖南 长沙 410013Department of Breast Thyroid Surgery, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - 刚 李
- />中南大学湘雅三医院乳甲外科，湖南 长沙 410013Department of Breast Thyroid Surgery, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - 丽丹 柳
- />中南大学湘雅三医院乳甲外科，湖南 长沙 410013Department of Breast Thyroid Surgery, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - 珊 黄
- />中南大学湘雅三医院乳甲外科，湖南 长沙 410013Department of Breast Thyroid Surgery, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - 俊 李
- />中南大学湘雅三医院乳甲外科，湖南 长沙 410013Department of Breast Thyroid Surgery, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - 唯 吴
- />中南大学湘雅三医院乳甲外科，湖南 长沙 410013Department of Breast Thyroid Surgery, Third Xiangya Hospital of Central South University, Changsha 410013, China
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Liu Y, Zhang L, Hu N, Shao J, Yang D, Ruan C, Huang S, Wang L, Lu WW, Zhang X, Yang F. An optogenetic approach for regulating human parathyroid hormone secretion. Nat Commun 2022; 13:771. [PMID: 35140213 PMCID: PMC8828854 DOI: 10.1038/s41467-022-28472-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 01/25/2022] [Indexed: 02/08/2023] Open
Abstract
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. Parathyroid hormone (PTH) plays a role in maintaining calcium and phosphorus homeostasis, and in secondary hyperparathyroidism excess PTH secretion contributes to bone loss. Here the authors report an optogenetic approach to inhibit PTH secretion in human hyperplastic parathyroid cells, and prevented hyperplastic parathyroid tissue-induced bone loss in mice.
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Affiliation(s)
- Yunhui Liu
- The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Lu Zhang
- The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.,Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong SAR, China
| | - Nan Hu
- Department of Nephrology and Shenzhen Key Laboratory of Kidney Diseases, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
| | - Jie Shao
- The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Dazhi Yang
- Department of Orthopedics, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, China
| | - Changshun Ruan
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen, China
| | - Shishu Huang
- Department of Orthopaedic Surgery and Orthopaedic Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Liping Wang
- The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China
| | - William W Lu
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong SAR, China
| | - Xinzhou Zhang
- Department of Nephrology and Shenzhen Key Laboratory of Kidney Diseases, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China.
| | - Fan Yang
- The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China. .,University of Chinese Academy of Sciences, Beijing, China.
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Koh J, Zhang R, Roman S, Duh QY, Gosnell J, Shen W, Suh I, Sosa JA. Ex Vivo Intact Tissue Analysis Reveals Alternative Calcium-sensing Behaviors in Parathyroid Adenomas. J Clin Endocrinol Metab 2021; 106:3168-3183. [PMID: 34272844 PMCID: PMC8530711 DOI: 10.1210/clinem/dgab524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT The biochemical basis for clinical variability in primary hyperparathyroidism (PHPT) is poorly understood. OBJECTIVE This study aimed to define parathyroid tumor biochemical properties associated with calcium-sensing failure in PHPT patients, and to relate differences in these profiles to variations in clinical presentation. METHODS Preoperative clinical data from a sequential series of 39 patients undergoing surgery for PHPT at an endocrine surgery referral center in a large, public university hospital were evaluated for correlation to parathyroid tumor biochemical behavior. An intact tissue, ex vivo interrogative assay was employed to evaluate the calcium-sensing capacity of parathyroid adenomas relative to normal donor glands. Tumors were functionally classified based on calcium dose-response curve profiles, and clinical parameters were compared among the respective classes. Changes in the relative expression of 3 key components in the calcium/parathyroid hormone (PTH) signaling axis-CASR, RGS5, and RCAN1-were evaluated as potential mechanisms for calcium-sensing failure. RESULTS Parathyroid adenomas grouped into 3 distinct functional classes. Tumors with diminished calcium sensitivity were the most common (18 of 39) and were strongly associated with reduced bone mineral density (P = 0.0009). Tumors with no calcium-sensing deficit (11 of 39) were associated with higher preoperative PTH (P = 0.036). A third group (6/39) displayed a nonsigmoid calcium/PTH response curve; 4 of these 6 tumors expressed elevated RCAN1. CONCLUSION Calcium-sensing capacity varies among parathyroid tumors but downregulation of the calcium-sensing receptor (CASR) is not an obligate underlying mechanism. Differences in tumor calcium responsiveness may contribute to variations in PHPT clinical presentation.
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Affiliation(s)
- James Koh
- Endocrine Neoplasia Laboratory, Department of Surgery, University of California
at San Francisco, San Francisco, CA, USA
- Department of Surgery, University of California at San Francisco,
San Francisco, CA, USA
| | - Run Zhang
- Endocrine Neoplasia Laboratory, Department of Surgery, University of California
at San Francisco, San Francisco, CA, USA
| | - Sanziana Roman
- Department of Surgery, University of California at San Francisco,
San Francisco, CA, USA
| | - Quan-Yang Duh
- Department of Surgery, University of California at San Francisco,
San Francisco, CA, USA
| | - Jessica Gosnell
- Department of Surgery, University of California at San Francisco,
San Francisco, CA, USA
| | - Wen Shen
- Department of Surgery, University of California at San Francisco,
San Francisco, CA, USA
| | - Insoo Suh
- Department of Surgery, NYU Langone Health, New York,
NY, USA
| | - Julie A Sosa
- Endocrine Neoplasia Laboratory, Department of Surgery, University of California
at San Francisco, San Francisco, CA, USA
- Department of Surgery, University of California at San Francisco,
San Francisco, CA, USA
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22
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Schmidt GS, Weaver TD, Hoang TD, Shakir MK. Severe Symptomatic Hypocalcemia, complicating cardiac arrhythmia following Cinacalcet (Sensipar TM) administration: A Case Report. Clin Case Rep 2021; 9:e04876. [PMID: 34659755 PMCID: PMC8502441 DOI: 10.1002/ccr3.4876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/02/2021] [Accepted: 09/09/2021] [Indexed: 11/29/2022] Open
Abstract
Clinicians should closely monitor patients on calcimimetics for hypocalcemic symptoms and arrhythmia, even though asymptomatic hypocalcemia typically resolves without intervention.
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Affiliation(s)
- Gregory S. Schmidt
- Department of EndocrinologyWalter Reed National Military Medical CenterBethesdaMDUSA
| | - Travis D. Weaver
- Department of EndocrinologyWalter Reed National Military Medical CenterBethesdaMDUSA
| | - Thanh D. Hoang
- Department of EndocrinologyWalter Reed National Military Medical CenterBethesdaMDUSA
| | - Mohamed K.M. Shakir
- Department of EndocrinologyWalter Reed National Military Medical CenterBethesdaMDUSA
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23
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Investigation of single nucleotide polymorphism in TSH-β and CaSR associated with body weight in Korean native chickens (Gray Brown). JOURNAL OF ANIMAL REPRODUCTION AND BIOTECHNOLOGY 2021. [DOI: 10.12750/jarb.36.3.129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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24
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Connelly MK, Cheng AA, Hernandez LL. Graduate Student Literature Review: Serotonin and calcium metabolism: A story unfolding. J Dairy Sci 2021; 104:13008-13019. [PMID: 34531048 DOI: 10.3168/jds.2021-20610] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/26/2021] [Indexed: 12/25/2022]
Abstract
The peripartum period is characterized by dynamic shifts in metabolic, mineral, and immune metabolism as the dairy cow adapts to the demands of lactation. Emphasis over the past decade has been placed on understanding the biology of the large shift in calcium metabolism in particular. Moreover, research has also focused on exploring the role of serotonin during the transition period and lactation and further unraveling its relationship with calcium. This review aimed to demonstrate the integration of calcium physiology during the peripartal period and throughout lactation. More specifically, we sought to discuss the knowledge gained in recent years on calcium metabolism, mammary calcium transport, serotonin metabolism, and the serotonin-calcium axis. Herein we also discuss the challenges and limitations of current research and where that leaves the present understanding of the serotonin-calcium axis as we seek to move forward and continue exploring this interesting relationship.
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Affiliation(s)
- M K Connelly
- Department of Animal and Dairy Sciences, University of Wisconsin, Madison 53706.
| | - A A Cheng
- Department of Animal and Dairy Sciences, University of Wisconsin, Madison 53706
| | - L L Hernandez
- Department of Animal and Dairy Sciences, University of Wisconsin, Madison 53706
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25
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Kalinkovich A, Livshits G. Biased and allosteric modulation of bone cell-expressing G protein-coupled receptors as a novel approach to osteoporosis therapy. Pharmacol Res 2021; 171:105794. [PMID: 34329703 DOI: 10.1016/j.phrs.2021.105794] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/20/2021] [Accepted: 07/25/2021] [Indexed: 12/16/2022]
Abstract
On the cellular level, osteoporosis (OP) is a result of imbalanced bone remodeling, in which osteoclastic bone resorption outcompetes osteoblastic bone formation. Currently available OP medications include both antiresorptive and bone-forming drugs. However, their long-term use in OP patients, mainly in postmenopausal women, is accompanied by severe side effects. Notably, the fundamental coupling between bone resorption and formation processes underlies the existence of an undesirable secondary outcome that bone anabolic or anti-resorptive drugs also reduce bone formation. This drawback requires the development of anti-OP drugs capable of selectively stimulating osteoblastogenesis and concomitantly reducing osteoclastogenesis. We propose that the application of small synthetic biased and allosteric modulators of bone cell receptors, which belong to the G-protein coupled receptors (GPCR) family, could be the key to resolving the undesired anti-OP drug selectivity. This approach is based on the capacity of these GPCR modulators, unlike the natural ligands, to trigger signaling pathways that promote beneficial effects on bone remodeling while blocking potentially deleterious effects. Under the settings of OP, an optimal anti-OP drug should provide fine-tuned regulation of downstream effects, for example, intermittent cyclic AMP (cAMP) elevation, preservation of Ca2+ balance, stimulation of osteoprotegerin (OPG) and estrogen production, suppression of sclerostin secretion, and/or preserved/enhanced canonical β-catenin/Wnt signaling pathway. As such, selective modulation of GPCRs involved in bone remodeling presents a promising approach in OP treatment. This review focuses on the evidence for the validity of our hypothesis.
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Affiliation(s)
- Alexander Kalinkovich
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6905126, Israel
| | - Gregory Livshits
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6905126, Israel; Adelson School of Medicine, Ariel University, Ariel 4077625, Israel.
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26
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Schumacher SA, Kamr AM, Lakritz J, Burns TA, Bertone AL, Toribio RE. Effects of intravenous magnesium sulfate on serum calcium-regulating hormones and plasma and urinary electrolytes in healthy horses. PLoS One 2021; 16:e0247542. [PMID: 34181644 PMCID: PMC8238178 DOI: 10.1371/journal.pone.0247542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 05/21/2021] [Indexed: 11/29/2022] Open
Abstract
Intravenous magnesium sulfate (MgSO4) is used in equine practice to treat hypomagnesemia, dysrhythmias, neurological disorders, and calcium dysregulation. MgSO4 is also used as a calming agent in equestrian events. Hypercalcemia affects calcium-regulating hormones, as well as plasma and urinary electrolytes; however, the effect of hypermagnesemia on these variables is unknown. The goal of this study was to investigate the effect of hypermagnesemia on blood parathyroid hormone (PTH), calcitonin (CT), ionized calcium (Ca2+), ionized magnesium (Mg2+), sodium (Na+), potassium (K+), chloride (Cl-) and their urinary fractional excretion (F) after intravenous administration of MgSO4 in healthy horses. Twelve healthy female horses of 4–18 years of age and 432–600 kg of body weight received a single intravenous dose of MgSO4 (60 mg/kg) over 5 minutes, and blood and urine samples were collected at different time points over 360 minutes. Plasma Mg2+ concentrations increased 3.7-fold over baseline values at 5 minutes and remained elevated for 120 minutes (P < 0.05), Ca2+ concentrations decreased from 30–60 minutes (P < 0.05), but Na+, K+ and Cl- concentrations did not change. Serum PTH concentrations dropped initially to rebound and remain elevated from 30 to 60 minutes, while CT concentrations increased at 5 minutes to return to baseline by 10 minutes (P < 0.05). The FMg, FCa, FNa, FK, and FCl increased, while urine osmolality decreased from 30–60 minutes compared baseline (P < 0.05). Short-term experimental hypermagnesemia alters calcium-regulating hormones (PTH, CT), reduces plasma Ca2+ concentrations, and increases the urinary excretion of Mg2+, Ca2+, K+, Na+ and Cl- in healthy horses. This information has clinical implications for the short-term effects of hypermagnesemia on calcium-regulation, electrolytes, and neuromuscular activity, in particular with increasing use of Mg salts to treat horses with various acute and chronic conditions as well as a calming agent in equestrian events.
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Affiliation(s)
- Stephen A. Schumacher
- College of Veterinary Medicine, The Ohio State University, Columbus, OH, United States of America
- United States Equestrian Federation, Columbus, Ohio, United States of America
| | - Ahmed M. Kamr
- College of Veterinary Medicine, The Ohio State University, Columbus, OH, United States of America
- Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Jeffrey Lakritz
- College of Veterinary Medicine, The Ohio State University, Columbus, OH, United States of America
| | - Teresa A. Burns
- College of Veterinary Medicine, The Ohio State University, Columbus, OH, United States of America
| | - Alicia L. Bertone
- College of Veterinary Medicine, The Ohio State University, Columbus, OH, United States of America
| | - Ramiro E. Toribio
- College of Veterinary Medicine, The Ohio State University, Columbus, OH, United States of America
- * E-mail:
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27
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Abid HA, Inoue A, Gorvin CM. Heterogeneity of G protein activation by the calcium-sensing receptor. J Mol Endocrinol 2021; 67:41-53. [PMID: 34077389 PMCID: PMC8240730 DOI: 10.1530/jme-21-0058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/02/2021] [Indexed: 12/20/2022]
Abstract
The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a fundamental role in extracellular calcium (Ca2+e) homeostasis by regulating parathyroid hormone release and urinary calcium excretion. The CaSR has been described to activate all four G protein subfamilies (Gαq/11, Gαi/o, Gα12/13, Gαs), and mutations in the receptor that cause hyper/hypocalcaemia, have been described to bias receptor signalling. However, many of these studies are based on measurements of second messengers or gene transcription that occurs many steps downstream of receptor activation and can represent convergence points of several signalling pathways. Therefore, to assess CaSR-mediated G protein activation directly, we took advantage of a recently described NanoBiT G protein dissociation assay system. Our studies, performed in HEK293 cells stably expressing CaSR, demonstrate that Ca2+e stimulation activates all Gαq/11 family and several Gαi/o family proteins, although Gαz was not activated. CaSR stimulated dissociation of Gα12/13 and Gαs from Gβ-subunits, but this occurred at a slower rate than that of other Gα-subunits. Investigation of cDNA expression of G proteins in three tissues abundantly expressing CaSR, the parathyroids, kidneys and pancreas, showed Gα11, Gαz, Gαi1 and Gα13 genes were highly expressed in parathyroid tissue, indicating CaSR most likely activates Gα11 and Gαi1 in parathyroids. In kidney and pancreas, the majority of G proteins were similarly expressed, suggesting CaSR may activate multiple G proteins in these cells. Thus, these studies validate a single assay system that can be used to robustly assess CaSR variants and biased signalling and could be utilised in the development of new pharmacological compounds targeting CaSR.
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Affiliation(s)
- Hasnat Ali Abid
- Institute of Metabolism and Systems Research and Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK
| | - Asuka Inoue
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Caroline M Gorvin
- Institute of Metabolism and Systems Research and Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK
- Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, UK
- Correspondence should be addressed to C M Gorvin:
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28
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Zimpel R, Nehme Marinho M, Almeida KV, Ruiz AR, Nelson CD, Thatcher WW, Santos JEP. Effects of maternal level of dietary cation-anion difference fed to prepartum nulliparous cows on offspring acid-base balance, metabolism, and growth. J Dairy Sci 2021; 104:8746-8764. [PMID: 34053764 DOI: 10.3168/jds.2021-20483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 04/07/2021] [Indexed: 01/18/2023]
Abstract
The objectives were to determine the effects of dietary cation-anion difference (DCAD) fed to pregnant cows during the last 22 d of gestation on offspring acid-base balance, metabolism, growth, and health preweaning. A total of 132 nulliparous Holstein cows were enrolled at 250 (248 to 253) d of gestation in a randomized block design. Cows were blocked by genomic merit of energy-corrected milk yield and assigned randomly to diets varying in DCAD: +200 (P200, n = 43), -50 (N50, n = 45), or -150 (N150, n = 44) mEq/kg of dry matter (DM). Newborn calves (15 males and 28 females in P200, 22 males and 23 females in N50, and 18 males and 26 females in N150) were followed for the first 7 or 56 d of age if males or females, respectively. Measures of acid-base balance and concentrations of minerals in blood were measured in all calves on d 0 before colostrum feeding, and on d 1, 3, and 7. Each calf was fed 3.78 L of colostrum from the respective treatment, and apparent efficiency of IgG absorption was determined. All calves were weighed at birth, and females were weighed again at 21, 42, and 56 d of age. Concentrations in serum of total calcium (tCa), total magnesium (tMg), and total phosphorus (tP) were measured up to 56 d of age; intakes of milk and starter grain DM were measured daily from 21 to 56 d of age; and incidence of disease was recorded for the first 56 d of age in females. Treatment did not affect acid-base balance measured in all calves. Calves were born with metabolic and respiratory acidosis, which reversed by 1 d of age. In the first 24 h after birth, blood pH increased from 7.215 to 7.421 and bicarbonate from 26.2 to 31.7 mM, whereas partial pressure of CO2 decreased from 64.1 to 48.7 mm of Hg in all treatments. Maternal DCAD did not affect colostrum IgG content fed to calves (P200 = 95.0 vs. N50 = 91.0 vs. N150 = 97.1 ± 4.1 g/L) or apparent efficiency of IgG absorption (P200 = 33.1 vs. N50 = 33.1 vs. N150 = 34.2 ± 1.9%). Males were born heavier than females, but maternal DCAD did not affect birth weight of all calves (P200 = 37.7 vs. N50 = 37.3 vs. N150 = 37.8 ± 0.7 kg) or daily weight gain in females in the first 56 d of life (P200 = 0.80 vs. N50 = 0.81 vs. N150 = 0.77 ± 0.03 kg/d). Treatment did not affect intake of milk (P200 = 1.11 vs. N50 = 1.04 vs. N150 = 1.19 ± 0.06 kg/d) or starter grain DM (P200 = 0.27 vs. N50 = 0.27 vs. N150 = 0.21 ± 0.06 kg/d), or measures of feed efficiency. Treatment did not affect concentrations of minerals in serum, morbidity, or age at morbidity. Manipulating the DCAD of pregnant nulliparous dams during late gestation did not affect offspring performance in the first 2 mo of age.
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Affiliation(s)
- R Zimpel
- Department of Animal Sciences, University of Florida, Gainesville, 32611; DH Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, 32611
| | - M Nehme Marinho
- Department of Animal Sciences, University of Florida, Gainesville, 32611
| | - K V Almeida
- Department of Animal Sciences, University of Florida, Gainesville, 32611
| | - A Revilla Ruiz
- Department of Animal Sciences, University of Florida, Gainesville, 32611
| | - C D Nelson
- Department of Animal Sciences, University of Florida, Gainesville, 32611
| | - W W Thatcher
- Department of Animal Sciences, University of Florida, Gainesville, 32611; DH Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, 32611
| | - J E P Santos
- Department of Animal Sciences, University of Florida, Gainesville, 32611; DH Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, 32611.
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29
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Hands JM, Moy LS. Calcium: More Than Bone? Implications for Clinical Practice and Theory. J Clin Med Res 2021; 13:253-257. [PMID: 34104276 PMCID: PMC8166293 DOI: 10.14740/jocmr4505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 05/08/2021] [Indexed: 11/25/2022] Open
Abstract
Serum calcium is routinely screened, but rarely scrutinized in the context of normal, physiologic functioning. This brief review strives to explore the implications of serum calcium, suggests guidelines for its interpretation, and discusses the implications of high, low, and “normocalcemia” in the clinical setting. We find that serum Ca2+ concentrations are a valuable prognostic indicator in routine metabolic workups and advocate for greater attention, on behalf of the provider, to variations in a patient’s calcemic status. Variations in calcemic status are primarily tied to malignancy, impaired parathyroid hormone (PTH) secretion, defects in vitamin D synthesis, insulin-like growth factor 1 (IGF-1) fluctuation, genetic syndromes (DiGeorge syndrome) and calcium-sensing receptor (CaSR) mutation. Prognostic implications for high and low serum Ca2+ include, but are not limited to, increased thromboembolic and major adverse cardiovascular event (MACE) risk, cardiac remodeling, hypertension, cognitive decline, and insulin resistance.
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Affiliation(s)
- Jacob M Hands
- South Bay Institute of Clinical Research, University of California, Berkeley, CA, USA
| | - Lawrence S Moy
- South Bay Institute of Clinical Research, University of California, Berkeley, CA, USA
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30
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Papadopoulou A, Bountouvi E, Karachaliou FE. The Molecular Basis of Calcium and Phosphorus Inherited Metabolic Disorders. Genes (Basel) 2021; 12:genes12050734. [PMID: 34068220 PMCID: PMC8153134 DOI: 10.3390/genes12050734] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 02/07/2023] Open
Abstract
Calcium (Ca) and Phosphorus (P) hold a leading part in many skeletal and extra-skeletal biological processes. Their tight normal range in serum mirrors their critical role in human well-being. The signalling “voyage” starts at Calcium Sensing Receptor (CaSR) localized on the surface of the parathyroid glands, which captures the “oscillations” of extracellular ionized Ca and transfers the signal downstream. Parathyroid hormone (PTH), Vitamin D, Fibroblast Growth Factor (FGF23) and other receptors or ion-transporters, work synergistically and establish a highly regulated signalling circuit between the bone, kidneys, and intestine to ensure the maintenance of Ca and P homeostasis. Any deviation from this well-orchestrated scheme may result in mild or severe pathologies expressed by biochemical and/or clinical features. Inherited disorders of Ca and P metabolism are rare. However, delayed diagnosis or misdiagnosis may cost patient’s quality of life or even life expectancy. Unravelling the thread of the molecular pathways involving Ca and P signaling, we can better understand the link between genetic alterations and biochemical and/or clinical phenotypes and help in diagnosis and early therapeutic intervention.
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31
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Gasmi A, Bjørklund G, Peana M, Mujawdiya PK, Pivina L, Ongenae A, Piscopo S, Severin B. Phosphocalcic metabolism and the role of vitamin D, vitamin K2, and nattokinase supplementation. Crit Rev Food Sci Nutr 2021; 62:7062-7071. [PMID: 33966563 DOI: 10.1080/10408398.2021.1910481] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Calcium is involved in bone metabolism, regulation of nerve signaling, and release of neurotransmitters. Phosphorus is a structural component of ATP, participates in metabolic energy regulation, and ensures stability to biological membranes and cells. Vitamin D and vitamin K are important for intestinal absorption and renal excretion of calcium and phosphorus. Vitamin D plays a regulatory role in bone formation, carbohydrate metabolism, immune responses, and cardiovascular regulation. Research has linked vitamin D deficiency to the development of diabetes mellitus, hypertension, cancer, and osteoporosis. Vitamin K has been associated with a reduced risk of osteoporosis, cancer, and cardiovascular diseases (due to improved vascular elasticity). This review highlights the importance of vitamins D and K in the metabolism of calcium and phosphorus and explores various molecular mechanisms that help maintain the system's mineral homeostasis. Moreover, the paper reviews the enzyme nattokinase's role in thrombotic prevention due to its fibrinolytic activity.
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Affiliation(s)
- Amin Gasmi
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France
| | - Geir Bjørklund
- Council for Nutritional and Environmental Medicine (CONEM), Mo i Rana, Norway
| | - Massimiliano Peana
- Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy
| | | | - Lyudmila Pivina
- Semey Medical University, Semey, Kazakhstan.,CONEM Kazakhstan Environmental Health and Safety Research Group, Semey Medical University, Semey, Kazakhstan
| | - Adrien Ongenae
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France
| | - Salva Piscopo
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France
| | - Beatrice Severin
- Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania
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32
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Brouns I, Verckist L, Pintelon I, Timmermans JP, Adriaensen D. Pulmonary Sensory Receptors. ADVANCES IN ANATOMY EMBRYOLOGY AND CELL BIOLOGY 2021; 233:1-65. [PMID: 33950466 DOI: 10.1007/978-3-030-65817-5_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Inge Brouns
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerpen (Wilrijk), Belgium.
| | - Line Verckist
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerpen (Wilrijk), Belgium
| | - Isabel Pintelon
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerpen (Wilrijk), Belgium
| | - Jean-Pierre Timmermans
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerpen (Wilrijk), Belgium
| | - Dirk Adriaensen
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerpen (Wilrijk), Belgium
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33
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Abstract
Magnesium (Mg2+) plays an essential role in many biological processes. Mg2+ deficiency is therefore associated with a wide range of clinical effects including muscle cramps, fatigue, seizures and arrhythmias. To maintain sufficient Mg2+ levels, (re)absorption of Mg2+ in the intestine and kidney is tightly regulated. Genetic defects that disturb Mg2+ uptake pathways, as well as drugs interfering with Mg2+ (re)absorption cause hypomagnesemia. The aim of this review is to provide an overview of the molecular mechanisms underlying genetic and drug-induced Mg2+ deficiencies. This leads to the identification of four main mechanisms that are affected by hypomagnesemia-causing mutations or drugs: luminal transient receptor potential melastatin type 6/7-mediated Mg2+ uptake, paracellular Mg2+ reabsorption in the thick ascending limb of Henle's loop, structural integrity of the distal convoluted tubule and Na+-dependent Mg2+ extrusion driven by the Na+/K+-ATPase. Our analysis demonstrates that genetic and drug-induced causes of hypomagnesemia share common molecular mechanisms. Targeting these shared pathways can lead to novel treatment options for patients with hypomagnesemia.
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Zavala-Barrera C, Del-Río-Robles JE, García-Jiménez I, Egusquiza-Alvarez CA, Hernández-Maldonado JP, Vázquez-Prado J, Reyes-Cruz G. The calcium sensing receptor (CaSR) promotes Rab27B expression and activity to control secretion in breast cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:119026. [PMID: 33845096 DOI: 10.1016/j.bbamcr.2021.119026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 12/11/2022]
Abstract
Chemotactic and angiogenic factors secreted within the tumor microenvironment eventually facilitate the metastatic dissemination of cancer cells. Calcium-sensing receptor (CaSR) activates secretory pathways in breast cancer cells via a mechanism driven by vesicular trafficking of this receptor. However, it remains to be elucidated how endosomal proteins in secretory vesicles are controlled by CaSR. In the present study, we demonstrate that CaSR promotes expression of Rab27B and activates this secretory small GTPase via PI3K, PKA, mTOR and MADD, a guanine nucleotide exchange factor, also known as DENN/Rab3GEP. Active Rab27B leads secretion of various cytokines and chemokines, including IL-6, IL-1β, IL-8, IP-10 and RANTES. Expression of Rab27B is stimulated by CaSR in MDA-MB-231 and MCF-7 breast epithelial cancer cells, but not in non-cancerous MCF-10A cells. This regulatory mechanism also occurs in HeLa and PC3 cells. Our findings provide insightful information regarding how CaSR activates a Rab27B-dependent mechanism to control secretion of factors known to intervene in paracrine communication circuits within the tumor microenvironment.
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Affiliation(s)
- Cesar Zavala-Barrera
- Departments of Cell Biology, Centro de Investigación y Estudios Avanzados del IPN (Cinvestav-IPN), Mexico City, Mexico
| | - Jorge Eduardo Del-Río-Robles
- Departments of Cell Biology, Centro de Investigación y Estudios Avanzados del IPN (Cinvestav-IPN), Mexico City, Mexico
| | - Irving García-Jiménez
- Departments of Cell Biology, Centro de Investigación y Estudios Avanzados del IPN (Cinvestav-IPN), Mexico City, Mexico
| | | | | | - José Vázquez-Prado
- Departments of Pharmacology, Centro de Investigación y Estudios Avanzados del IPN (Cinvestav-IPN), Mexico City, Mexico
| | - Guadalupe Reyes-Cruz
- Departments of Cell Biology, Centro de Investigación y Estudios Avanzados del IPN (Cinvestav-IPN), Mexico City, Mexico.
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Davies MP, John Evans TW, Tahir F, Balasubramanian SP. Parathyroid cancer: A systematic review of diagnostic biomarkers. Surgeon 2021; 19:e536-e548. [PMID: 33642204 DOI: 10.1016/j.surge.2021.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/27/2020] [Accepted: 01/12/2021] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Parathyroid cancers are rare and difficult to distinguish from benign parathyroid tumours. Prediction of malignancy often relies on intraoperative assessment of invasion. Standard histology is also inadequate; especially in the absence of local invasion, lymph nodal disease and metastasis. The aim of this project was to systematically review published literature on potential bio-markers used for the diagnosis of parathyroid cancer. METHODS Pubmed, Web of Science and Medline databases were searched. Inclusion criteria included English language papers published after 1985 and reporting on biomarkers in human studies of parathyroid cancer and benign disease. RESULTS 118 relevant papers were appraised; all were observational studies. At least 2 papers studied 8 serum, 4 urine and 27 tissue biomarkers on the diagnosis of parathyroid cancer. Of these, 5 serum and 13 tissue markers have been demonstrated in at least one study to be statistically different in benign and malignant disease. We present a synthesis of data for each biomarker and measures of diagnostic accuracy where possible. CONCLUSIONS Consideration should be given to the use of a panel of biomarkers to review patients with suspected parathyroid cancer. A profile including serum calcium and PTH levels and tissue expression of APC, Parafibromin, PGP9.5, Galectin 3 and Ki67 is proposed. Systematic Review Registration Number - CRD42019127833.
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Affiliation(s)
- Matthew Philip Davies
- Faculty of Medicine, Dentistry and Health, The University of Sheffield, United Kingdom.
| | | | - Fawzia Tahir
- Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom
| | - Saba P Balasubramanian
- Faculty of Medicine, Dentistry and Health, The University of Sheffield, United Kingdom; Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom
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Sundararaman SS, van der Vorst EPC. Calcium-Sensing Receptor (CaSR), Its Impact on Inflammation and the Consequences on Cardiovascular Health. Int J Mol Sci 2021; 22:2478. [PMID: 33804544 PMCID: PMC7957814 DOI: 10.3390/ijms22052478] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/11/2021] [Accepted: 02/25/2021] [Indexed: 12/15/2022] Open
Abstract
The calcium Sensing Receptor (CaSR) is a cell surface receptor belonging to the family of G-protein coupled receptors. CaSR is mainly expressed by parathyroid glands, kidneys, bone, skin, adipose tissue, the gut, the nervous system, and the cardiovascular system. The receptor, as its name implies is involved in sensing calcium fluctuations in the extracellular matrix of cells, thereby having a major impact on the mineral homeostasis in humans. Besides calcium ions, the receptor is also activated by other di- and tri-valent cations, polypeptides, polyamines, antibiotics, calcilytics and calcimimetics, which upon binding induce intracellular signaling pathways. Recent studies have demonstrated that CaSR influences a wide variety of cells and processes that are involved in inflammation, the cardiovascular system, such as vascular calcification, atherosclerosis, myocardial infarction, hypertension, and obesity. Therefore, in this review, the current understanding of the role that CaSR plays in inflammation and its consequences on the cardiovascular system will be highlighted.
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Affiliation(s)
- Sai Sahana Sundararaman
- Interdisciplinary Centre for Clinical Research (IZKF), RWTH Aachen University, 52074 Aachen, Germany;
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany
| | - Emiel P. C. van der Vorst
- Interdisciplinary Centre for Clinical Research (IZKF), RWTH Aachen University, 52074 Aachen, Germany;
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
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Hui Q, Zhao X, Lu P, Liu S, Nyachoti M, O K, Yang C. Molecular distribution and localization of extracellular calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) at three different laying stages in laying hens (Gallus gallus domesticus). Poult Sci 2021; 100:101060. [PMID: 33752067 PMCID: PMC8010884 DOI: 10.1016/j.psj.2021.101060] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 11/02/2020] [Accepted: 02/11/2021] [Indexed: 01/06/2023] Open
Abstract
The extracellular calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) play important roles in regulating calcium mobilization, calcium absorption, and calcium homeostasis, and they could be potential therapeutic targets to osteoporosis in laying hens. The present study investigated the molecular distribution of CaSR and VDR and the localization of CaSR in the kidney, proventriculus (true stomach), duodenum, jejunum, ileum, colon, cecum, shell gland, and tibia of laying hens at 3 different laying stages (19, 40, and 55 wk). The results showed that the relative mRNA abundance of CaSR in the kidney, ileum, proventriculus, duodenum, and colon was higher (P < 0.05) than the other tissues at 40 and 55 wk. The relative mRNA abundance of CaSR in the tibia was higher (P < 0.05) at 55 wk than at 40 wk. However, there were no significant differences in the relative protein abundance of CaSR among all tested tissues at peak production or in each tissue at the 3 different laying stages (P > 0.05). The relative mRNA abundance of VDR was higher (P < 0.05) in the small intestine (duodenum, jejunum, and ileum) when compared with other tissues at the 3 different laying stages. The relative protein abundance of VDR in the duodenum was higher (P < 0.05) than that in the proventriculus, colon, and cecum. There were no significant differences in the VDR expression among the tested tissues at the 3 different laying stages (P > 0.05). The immunohistochemical results showed that the positive staining was found widely in each tissue. Moreover, different laying stages did not affect the localization of CaSR except for the tibia tissue. In conclusion, similar to VDR, CaSR was widely expressed not only in the gut but also in the tibia and shell gland in laying hens. The expression level of CaSR and VDR in all tested tissues was unchanged at the different laying stages.
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Affiliation(s)
- Qianru Hui
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada
| | - Xiaoya Zhao
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada
| | - Peng Lu
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada
| | - Shangxi Liu
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada
| | - Martin Nyachoti
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada
| | - Karmin O
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada; CCARM, St. Boniface Hospital Research Centre, Winnipeg, Manitoba R2H 2A6, Canada
| | - Chengbo Yang
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada.
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Hao Y, Lei Z, Shi N, Yu L, Ji W, Zhang X. Radiofrequency Ablation of Parathyroid Glands to Treat a Patient With Hypercalcemia Caused by a Novel Inactivating Mutation in CaSR. Front Endocrinol (Lausanne) 2021; 12:743517. [PMID: 35095753 PMCID: PMC8795859 DOI: 10.3389/fendo.2021.743517] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 12/21/2021] [Indexed: 02/01/2023] Open
Abstract
OBJECTIVE We identified a novel inactivating mutation in the calcium-sensing receptor (CaSR) gene in a patient with refractory hypocalciuric hypercalcemia and analyzed its function. The effectiveness of radiofrequency ablation of the parathyroid glands to treat hypercalcemia caused by this mutation was explored. METHODS Clinical data of patients before and after radiofrequency ablation were retrospectively analyzed. The CaSR mutation (D99N) found in the patient was studied in cell lines. HEK-293 cells were transfected with plasmids containing wild-type (WT) or mutant CaSR genes (D99N and W718X). Expression levels of the respective CaSR proteins were measured, and their functions were assessed by examining the effect of NPS R-568 (a CaSR agonist) on intracellular Ca2+ oscillations and that of exogenous parathyroid hormone (PTH) on intracellular cyclic adenosine monophosphate (cAMP) levels. RESULTS The effectiveness of pharmacological treatment was poor, whereas radiofrequency ablation of the parathyroid glands resulted in controlled blood calcium and PTH levels in the patient. In cell lines, upon NPS R-568 administration, the amplitude of intracellular Ca2+ oscillations in the D99N group was lower than that in the WT group and higher than that in the W718X group. Upon administration of PTH, intracellular cAMP levels in the D99N group were higher than those in the WT group and lower than those in the W718X group. CONCLUSION The homozygous mutation D99N reduced CaSR activity and caused more severe hypocalciuric hypercalcemia. For patients with this type of hypercalcemia and poor response to pharmacological treatments, radiofrequency ablation of the parathyroid glands may be a suitable treatment option.
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Affiliation(s)
- Yu Hao
- Department of Endocrinology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhikai Lei
- Department of Ultrasound, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nanjing Shi
- Department of Endocrinology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingying Yu
- Department of Endocrinology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weiqin Ji
- Department of Endocrinology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xianfeng Zhang
- Department of Endocrinology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Xianfeng Zhang,
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Functional Exploration of the Pulmonary NEB ME. ADVANCES IN ANATOMY, EMBRYOLOGY, AND CELL BIOLOGY 2021; 233:31-67. [PMID: 33950469 DOI: 10.1007/978-3-030-65817-5_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Lo Giudice M, Mihalik B, Turi Z, Dinnyés A, Kobolák J. Calcilytic NPS 2143 Reduces Amyloid Secretion and Increases sAβPPα Release from PSEN1 Mutant iPSC-Derived Neurons. J Alzheimers Dis 2020; 72:885-899. [PMID: 31640098 PMCID: PMC6918902 DOI: 10.3233/jad-190602] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Despite numerous efforts and studies over the last three decades, Alzheimer’s disease (AD) remains a disorder not fully understood and incurable so far. Development of induced pluripotent stem cell (iPSC) technology to obtain terminally differentiated neurons from adult somatic cells revolutionized the study of AD, providing a powerful tool for modelling the disease and for screening candidate drugs. Indeed, iPSC reprogramming allowed generation of neurons from both sporadic and familial AD patients with the promise to recapitulate the early pathological mechanisms in vitro and to identify novel targets. Interestingly, NPS 2143, a negative allosteric modulator of the calcium sensing receptor, has been indicated as a possible therapeutic for AD. In the present study, we assessed the potential of our iPSC-based familial AD cellular model as a platform for drug testing. We found that iPSC-derived neurons respond to treatment with γ-secretase inhibitor, modifying the physiological amyloid-β protein precursor (AβPP) processing and amyloid-β (Aβ) secretion. Moreover, we demonstrated the expression of calcium sensing receptor (CaSR) protein in human neurons derived from healthy and familial AD subjects. Finally, we showed that calcilytic NPS 2143 induced a changing of Aβ and sAβPPα secreted into conditioned media and modulation of CaSR and PSEN1 expression at the plasma membrane of AD neurons. Overall, our findings suggest that NPS 2143 affects important AD processes in a relevant in vitro system of familial AD.
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Affiliation(s)
- Maria Lo Giudice
- BioTalentum Ltd., Gödöllő, Hungary.,Molecular Animal Biotechnology Laboratory, Szent István University, Gödöllő, Hungary
| | | | | | - András Dinnyés
- BioTalentum Ltd., Gödöllő, Hungary.,Molecular Animal Biotechnology Laboratory, Szent István University, Gödöllő, Hungary
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Vieira-Neto A, Leão IMR, Prim JG, Silva ACM, Nehme Marinho M, Zimpel R, Etheve S, Nelson CD, Santos JEP. Effect of duration of exposure to diets differing in dietary cation-anion difference on Ca metabolism after a parathyroid hormone challenge in dairy cows. J Dairy Sci 2020; 104:1018-1038. [PMID: 33162070 DOI: 10.3168/jds.2020-19127] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 07/29/2020] [Indexed: 11/19/2022]
Abstract
Objectives of the experiment were to determine the length of exposure to an acidogenic diet that would elicit changes in acid-base balance, mineral digestion, and response to parathyroid hormone (PTH)-induced changes in blood Ca and vitamin D3 in prepartum dairy cows. Nonlactating parous Holstein cows (n = 20) at 242 d of gestation were blocked by lactation (1 or >1) and pretreatment dry matter (DM) intake and, within block, they were randomly assigned to a diet with a dietary cation-anion difference (DCAD) of +200 mEq/kg of DM (DCAD +200) or an acidogenic diet with -150 mEq/kg of DM (DCAD -150). Water and DM intake were measured and blood was sampled daily. Urine was sampled every 3 h for 36 h, and then daily. During PTH challenges on d 3, 8, and 13, cows received i.v. PTH 1-34 fragment at 0.05 µg/kg of body weight every 20 min for 9 h to mimic the pulsatile release of endogenous PTH. Blood was sampled at 0 h, and hourly thereafter until 10 h, and at 12, 18, 24, 36, and 48 h relative to each challenge. Acid-base measures and concentrations of ionized Ca (iCa) in whole blood, and total Ca, Mg, P, and vitamin D metabolites in plasma were evaluated. On d 2 and 7, Ca, Mg, and P balances were evaluated. Cows fed DCAD -150 had smaller blood pH (7.431 vs. 7.389) and HCO3- (27.4 vs. 22.8 mM) compared with DCAD +200, and metabolic acidosis in DCAD -150 was observed 24 h after dietary treatments started. Concentrations of iCa begin to increase 24 h after feeding the acidogenic diet, and it was greater in DCAD -150 compared with DCAD +200 by 3 d in the experiment (1.23 vs. 1.26 mM). During the PTH challenges, cows fed DCAD -150 had greater concentration of iCa and area under the curve for iCa than those fed DCAD +200 (48.2 vs. 50.7 mmol/L × hour), and there was no interaction between treatment and challenge day. Concentration of 1,25-dihydroxyvitamin D3 in plasma did not differ during the PTH challenge, but change in 1,25-dihydroxyvitamin D3 relative to h 0 of the challenge was smaller in cows fed DCAD -150 than cows fed DCAD +200 (44.1 vs. 32.9 pg/mL). Urinary loss of Ca was greater in cows fed DCAD -150 compared with DCAD +200 (1.8 vs. 10.8 g/d); however, because digestibility of Ca increased in cows fed DCAD -150 (19.7 vs. 36.6%), the amount of Ca retained did not differ between treatments. Diet-induced metabolic acidosis was observed by 24 h after dietary treatment started, resulting in increases in concentration of iCa in blood observed between 1 and 3 d. Collectively, present results indicate that tissue responsiveness to PTH and changes in blood concentrations of iCa and digestibility of Ca are elicited within 3 d of exposure to an acidogenic diet. The increased apparent digestibility of Ca compensated for the increased urinary loss of Ca resulting in similar Ca retention.
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Affiliation(s)
- A Vieira-Neto
- Department of Animal Sciences, University of Florida, Gainesville 32611; DH Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville 32611
| | - I M R Leão
- Department of Animal Sciences, University of Florida, Gainesville 32611
| | - J G Prim
- Department of Animal Sciences, University of Florida, Gainesville 32611
| | - A C M Silva
- Department of Animal Sciences, University of Florida, Gainesville 32611
| | - M Nehme Marinho
- Department of Animal Sciences, University of Florida, Gainesville 32611
| | - R Zimpel
- Department of Animal Sciences, University of Florida, Gainesville 32611; DH Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville 32611
| | - S Etheve
- DSM Nutritional Products Ltd., Basel, 4002 Switzerland
| | - C D Nelson
- Department of Animal Sciences, University of Florida, Gainesville 32611
| | - J E P Santos
- Department of Animal Sciences, University of Florida, Gainesville 32611; DH Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville 32611.
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Lawton BR, Martineau C, Sosa JA, Roman S, Gibson CE, Levine MA, Krause DS. Differentiation of PTH-Expressing Cells From Human Pluripotent Stem Cells. Endocrinology 2020; 161:5893997. [PMID: 32810225 PMCID: PMC7505176 DOI: 10.1210/endocr/bqaa141] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 08/07/2020] [Indexed: 12/13/2022]
Abstract
Differentiation of pluripotent stem cells into functional parathyroid-like cells would accelerate development of important therapeutic options for subjects with parathyroid-related disorders, from the design and screening of novel pharmaceutical agents to the development of durable cellular therapies. We have established a highly reproducible directed differentiation approach leading to PTH-expressing cells from human embryonic stem cells and induced pluripotent stem cells. We accomplished this through the comparison of multiple different basal media, the inclusion of the CDK inhibitor PD0332991 in both definitive endoderm and anterior foregut endoderm stages, and a 2-stage pharyngeal endoderm series. This is the first protocol to reproducibly establish PTH-expressing cells from human pluripotent stem cells and represents a first step toward the development of functional parathyroid cells with broad applicability for medicinal and scientific investigation.
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Affiliation(s)
- Betty R Lawton
- Department of Laboratory Medicine, Yale Stem Cell Center, Yale University, New Haven, Connecticut
| | - Corine Martineau
- Center for Bone Health and Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Julie Ann Sosa
- Department of Surgery, University of California San Francisco, San Francisco, California
| | - Sanziana Roman
- Department of Surgery, University of California San Francisco, San Francisco, California
| | | | - Michael A Levine
- Center for Bone Health and Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Diane S Krause
- Department of Laboratory Medicine, Cell Biology, Yale Stem Cell Center, Yale University, New Haven, Connecticut
- Department of Pathology, Yale Stem Cell Center, Yale University, New Haven, Connecticut
- Correspondence: Diane S. Krause, Yale University, Yale Stem Cell Center, 333 Cedar Street, New Haven, Connecticut 06520-8035, USA. E-mail:
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Leach K, Hannan FM, Josephs TM, Keller AN, Møller TC, Ward DT, Kallay E, Mason RS, Thakker RV, Riccardi D, Conigrave AD, Bräuner-Osborne H. International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function. Pharmacol Rev 2020; 72:558-604. [PMID: 32467152 PMCID: PMC7116503 DOI: 10.1124/pr.119.018531] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, γ-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca2+ o, an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via Gq/11, Gi/o, potentially G12/13, and even Gs in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. SIGNIFICANCE STATEMENT: The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.
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Affiliation(s)
- Katie Leach
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Fadil M Hannan
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Tracy M Josephs
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Andrew N Keller
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Thor C Møller
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Donald T Ward
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Enikö Kallay
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Rebecca S Mason
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Rajesh V Thakker
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Daniela Riccardi
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Arthur D Conigrave
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
| | - Hans Bräuner-Osborne
- Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.)
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Onopiuk M, Eby B, Nesin V, Ngo P, Lerner M, Gorvin CM, Stokes VJ, Thakker RV, Brandi ML, Chang W, Humphrey MB, Tsiokas L, Lau K. Control of PTH secretion by the TRPC1 ion channel. JCI Insight 2020; 5:132496. [PMID: 32213715 PMCID: PMC7205425 DOI: 10.1172/jci.insight.132496] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 03/16/2020] [Indexed: 11/17/2022] Open
Abstract
Familial hypocalciuric hypercalcemia (FHH) is a genetic condition associated with hypocalciuria, hypercalcemia, and, in some cases, inappropriately high levels of circulating parathyroid hormone (PTH). FHH is associated with inactivating mutations in the gene encoding the Ca2+-sensing receptor (CaSR), a GPCR, and GNA11 encoding G protein subunit α 11 (Gα11), implicating defective GPCR signaling as the root pathophysiology for FHH. However, the downstream mechanism by which CaSR activation inhibits PTH production/secretion is incompletely understood. Here, we show that mice lacking the transient receptor potential canonical channel 1 (TRPC1) develop chronic hypercalcemia, hypocalciuria, and elevated PTH levels, mimicking human FHH. Ex vivo and in vitro studies revealed that TRPC1 serves a necessary and sufficient mediator to suppress PTH secretion from parathyroid glands (PTGs) downstream of CaSR in response to high extracellular Ca2+ concentration. Gα11 physically interacted with both the N- and C-termini of TRPC1 and enhanced CaSR-induced TRPC1 activity in transfected cells. These data identify TRPC1-mediated Ca2+ signaling as an essential component of the cellular apparatus controlling PTH secretion in the PTG downstream of CaSR.
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Affiliation(s)
| | - Bonnie Eby
- Department of Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | | | | | - Megan Lerner
- Department of Surgery, Oklahoma City, Oklahoma, USA
| | - Caroline M Gorvin
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Victoria J Stokes
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Rajesh V Thakker
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Maria Luisa Brandi
- Department of Biomedicals Sperimentals and Clinicals Sciences, Università degli Studi di Firenze and Fondazione FIRMO, Florence, Italy
| | - Wenhan Chang
- Endocrinology and Metabolism, Department of Medicine, UCSF, San Francisco, California, USA
| | - Mary Beth Humphrey
- Department of Medicine, Division of Rheumatology, Immunology, and Allergy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.,Department of Veterans Affairs, Oklahoma City, Oklahoma, USA
| | | | - Kai Lau
- Department of Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.,Department of Veterans Affairs, Oklahoma City, Oklahoma, USA
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Parathyroid Hormone: A Uremic Toxin. Toxins (Basel) 2020; 12:toxins12030189. [PMID: 32192220 PMCID: PMC7150960 DOI: 10.3390/toxins12030189] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/08/2020] [Accepted: 03/08/2020] [Indexed: 12/27/2022] Open
Abstract
Parathyroid hormone (PTH) has an important role in the maintenance of serum calcium levels. It activates renal 1α-hydroxylase and increases the synthesis of the active form of vitamin D (1,25[OH]2D3). PTH promotes calcium release from the bone and enhances tubular calcium resorption through direct action on these sites. Hallmarks of secondary hyperparathyroidism associated with chronic kidney disease (CKD) include increase in serum fibroblast growth factor 23 (FGF-23), reduction in renal 1,25[OH]2D3 production with a decline in its serum levels, decrease in intestinal calcium absorption, and, at later stages, hyperphosphatemia and high levels of PTH. In this paper, we aim to critically discuss severe CKD-related hyperparathyroidism, in which PTH, through calcium-dependent and -independent mechanisms, leads to harmful effects and manifestations of the uremic syndrome, such as bone loss, skin and soft tissue calcification, cardiomyopathy, immunodeficiency, impairment of erythropoiesis, increase of energy expenditure, and muscle weakness.
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Lazrak A, Yu Z, Doran S, Jian MY, Creighton J, Laube M, Garantziotis S, Prakash YS, Matalon S. Upregulation of airway smooth muscle calcium-sensing receptor by low-molecular-weight hyaluronan. Am J Physiol Lung Cell Mol Physiol 2020; 318:L459-L471. [PMID: 31913654 PMCID: PMC7099432 DOI: 10.1152/ajplung.00429.2019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/29/2019] [Accepted: 12/31/2019] [Indexed: 12/19/2022] Open
Abstract
We investigated the mechanisms involved in the development of airway hyperresponsiveness (AHR) following exposure of mice to halogens. Male mice (C57BL/6; 20-25 g) exposed to either bromine (Br2) or Cl2 (600 or 400 ppm, respectively, for 30 min) developed AHR 24 h after exposure. Nifedipine (5 mg/kg body wt; an L-type calcium channel blocker), administered subcutaneously after Br2 or Cl2 exposure, produced higher AHR compared with Br2 or Cl2 alone. In contrast, diltiazem (5 mg/kg body wt; a nondihydropyridine L-type calcium channel blocker) decreased AHR to control (air) values. Exposure of immortalized human airway smooth muscle cells (hASMC) to Br2 resulted in membrane potential depolarization (Vm Air: 62 ± 3 mV; 3 h post Br2:-45 ± 5 mV; means ± 1 SE; P < 0.001), increased intracellular [Ca2+]i, and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br2 and nifedipine-induced Vm depolarization and [Ca2+]i increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br2 reversed the effects of Br2 and nifedipine on AHR. Incubation of hASMC with low-molecular-weight hyaluronan (LMW-HA), generated by exposing high-molecular-weight hyaluronan (HMW-HA) to Br2, caused Vm depolarization, [Ca2+]i increase, and Ca-SR expression to a similar extent as exposure to Br2 and Cl2. The addition of HMW-HA to cells or mice exposed to Br2, Cl2, or LMW-HA reversed these effects in vitro and improved AHR in vivo. We conclude that detrimental effects of halogen exposure on AHR are mediated via activation of the Ca-SR by LMW-HA.
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Affiliation(s)
- Ahmed Lazrak
- Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Zhihong Yu
- Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Stephen Doran
- Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Ming-Yuan Jian
- Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Judy Creighton
- Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Mandy Laube
- Department of Pediatrics, Division of Neonatology, Leipzig University, Leipzig, Germany
| | - Stavros Garantziotis
- Matrix Biology Group, Immunity, Inflammation, and Disease Laboratory, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Y S Prakash
- Department of Physiology and Biomedical Engineering and Anesthesiology, Mayo Clinic Alix School of Medicine and Science, Rochester, Minnesota
| | - Sadis Matalon
- Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama
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Sensing Extracellular Calcium - An Insight into the Structure and Function of the Calcium-Sensing Receptor (CaSR). ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1131:1031-1063. [PMID: 31646544 DOI: 10.1007/978-3-030-12457-1_41] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a key role in calcium homeostasis, by sensing free calcium levels in blood and regulating parathyroid hormone secretion in response. The CaSR is highly expressed in parathyroid gland and kidney where its role is well characterised, but also in other tissues where its function remains to be determined. The CaSR can be activated by a variety of endogenous ligands, as well as by synthetic modulators such as Cinacalcet, used in the clinic to treat secondary hyperparathyroidism in patients with chronic kidney disease. The CaSR couples to multiple G proteins, in a tissue-specific manner, activating several signalling pathways and thus regulating diverse intracellular events. The multifaceted nature of this receptor makes it a valuable therapeutic target for calciotropic and non-calciotropic diseases. It is therefore essential to understand the complexity behind the pharmacology, trafficking, and signalling characteristics of this receptor. This review provides an overview of the latest knowledge about the CaSR and discusses future hot topics in this field.
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Elajnaf T, Iamartino L, Mesteri I, Müller C, Bassetto M, Manhardt T, Baumgartner-Parzer S, Kallay E, Schepelmann M. Nutritional and Pharmacological Targeting of the Calcium-Sensing Receptor Influences Chemically Induced Colitis in Mice. Nutrients 2019; 11:E3072. [PMID: 31888253 PMCID: PMC6950720 DOI: 10.3390/nu11123072] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 12/12/2019] [Accepted: 12/13/2019] [Indexed: 01/19/2023] Open
Abstract
The calcium-sensing receptor (CaSR) is the main regulator of extracellular Ca2+ homeostasis. It has diverse functions in different tissues, including the intestines. Intestine-specific knockout of the CaSR renders mice more susceptible to dextran sulphate sodium (DSS)-induced colitis. To test our hypothesis that the CaSR reduces intestinal inflammation, we assessed the effects of nutritional and pharmacological agonists of the CaSR in a colitis model. We treated female Balb/C mice with dietary calcium and protein (nutritional agonists of the CaSR) or pharmacological CaSR modulators (the agonists cinacalcet and GSK3004774, and the antagonist NPS-2143; 10 mg/kg), then induced colitis with DSS. The high-protein diet had a strong pro-inflammatory effect-it shortened the colons (5.3 ± 0.1 cm vs. 6.1 ± 0.2 cm normal diet, p < 0.05), lowered mucin expression and upregulated pro-inflammatory cytokines, such as interferon-γ, (4.2-fold, p < 0.05) compared with the normal diet. Cinacalcet reduced mucin expression, which coincided with an increase in tumor necrosis factor-α (4.4-fold, p < 0.05) and IL-6 (4.9-fold, p < 0.05) in the plasma, compared with vehicle. The CaSR antagonist, NPS-2143, significantly reduced the cumulative inflammation score compared with the vehicle control (35.3 ± 19.1 vs. 21.9 ± 14.3 area under the curve, p < 0.05) and reduced infiltration of inflammatory cells. While dietary modulation of the CaSR had no beneficial effects, pharmacological inhibition of the CaSR may have the potential of a novel add-on therapy in the treatment of inflammatory bowel diseases.
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Affiliation(s)
- Taha Elajnaf
- Center of Pathophysiology Infectiology and Immunology, Medical University of Vienna, Pathophysiology and Allergy Research, Währinger Gürtel, 18-20, 1090 Vienna, Austria; (T.E.); (L.I.); (C.M.); (T.M.); (M.S.)
| | - Luca Iamartino
- Center of Pathophysiology Infectiology and Immunology, Medical University of Vienna, Pathophysiology and Allergy Research, Währinger Gürtel, 18-20, 1090 Vienna, Austria; (T.E.); (L.I.); (C.M.); (T.M.); (M.S.)
| | | | - Christian Müller
- Center of Pathophysiology Infectiology and Immunology, Medical University of Vienna, Pathophysiology and Allergy Research, Währinger Gürtel, 18-20, 1090 Vienna, Austria; (T.E.); (L.I.); (C.M.); (T.M.); (M.S.)
| | - Marcella Bassetto
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, CF10 3NB Cardiff, UK
- Department of Chemistry, College of Science, Swansea University, SA2 8PP Swansea, UK
| | - Teresa Manhardt
- Center of Pathophysiology Infectiology and Immunology, Medical University of Vienna, Pathophysiology and Allergy Research, Währinger Gürtel, 18-20, 1090 Vienna, Austria; (T.E.); (L.I.); (C.M.); (T.M.); (M.S.)
| | | | - Enikö Kallay
- Center of Pathophysiology Infectiology and Immunology, Medical University of Vienna, Pathophysiology and Allergy Research, Währinger Gürtel, 18-20, 1090 Vienna, Austria; (T.E.); (L.I.); (C.M.); (T.M.); (M.S.)
| | - Martin Schepelmann
- Center of Pathophysiology Infectiology and Immunology, Medical University of Vienna, Pathophysiology and Allergy Research, Währinger Gürtel, 18-20, 1090 Vienna, Austria; (T.E.); (L.I.); (C.M.); (T.M.); (M.S.)
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Minakata T, Inagaki A, Yamamura A, Yamamura H, Sekiya S, Murakami S. Calcium-Sensing Receptor Is Functionally Expressed in the Cochlear Perilymphatic Compartment and Essential for Hearing. Front Mol Neurosci 2019; 12:175. [PMID: 31379498 PMCID: PMC6648107 DOI: 10.3389/fnmol.2019.00175] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 07/01/2019] [Indexed: 11/26/2022] Open
Abstract
Maintaining Ca2+ homeostasis in lymphatic fluids is necessary for proper hearing. Despite its significance, the mechanisms that maintain the cochlear lymphatic Ca2+ concentrations within a certain range are not fully clarified. We investigated the functional expression of calcium-sensing receptor (CaSR), which plays a pivotal role in sensing extracellular Ca2+ concentrations for feedback regulations. Western blotting for CaSR revealed an approximately 130-kDa protein expression in cochlear tissue extracts and immunohistochemical analysis revealed its expression specifically in type I fibrocytes in the spiral ligament, fibrocytes in the supralimbal and limbal regions, the epithelium of the osseous spiral lamina, and the smooth muscle cells of the spiral modiolar arteries. Ca2+ imaging demonstrated that extracellular Ca2+ increased the levels of intracellular Ca2+ in CaSR-expressing fibrocytes in the spiral ligament, and that this was suppressed by the CaSR inhibitor, NPS2143. Furthermore, hearing thresholds were moderately elevated by intracochlear application of the CaSR inhibitors NPS2143 and Calhex231, across a range of frequencies (8–32 kHz). These results demonstrate the functional expression of CaSR in the cochlear perilymphatic compartment. In addition, the elevated hearing thresholds that are achieved by inhibiting CaSR suggest this is a required mechanism for normal hearing, presumably by sensing perilymphatic Ca2+ to stabilize Ca2+ concentrations within a certain range. These results provide novel insight into the mechanisms regulating Ca2+ homeostasis in the cochlea and provide a new perspective on cochlear physiology.
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Affiliation(s)
- Toshiya Minakata
- Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya, Japan
| | - Akira Inagaki
- Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya, Japan
| | - Aya Yamamura
- Department of Physiology, Aichi Medical University, Nagakute, Japan
| | - Hisao Yamamura
- Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
| | - Shinji Sekiya
- Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya, Japan
| | - Shingo Murakami
- Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya, Japan
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