-
Nature Reviews. Nephrology Oct 2023Two decades ago, Kidney Disease: Improving Global Outcomes coined the term chronic kidney disease-mineral and bone disorder (CKD-MBD) to describe the syndrome of... (Review)
Review
Two decades ago, Kidney Disease: Improving Global Outcomes coined the term chronic kidney disease-mineral and bone disorder (CKD-MBD) to describe the syndrome of biochemical, bone and extra-skeletal calcification abnormalities that occur in patients with CKD. CKD-MBD is a prevalent complication and contributes to the excessively high burden of fractures and cardiovascular disease, loss of quality of life and premature mortality in patients with CKD. Thus far, therapy has focused primarily on phosphate retention, abnormal vitamin D metabolism and parathyroid hormone disturbances, but these strategies have largely proved unsuccessful, thus calling for paradigm-shifting concepts and innovative therapeutic approaches. Interorgan crosstalk is increasingly acknowledged to have an important role in health and disease. Accordingly, mounting evidence suggests a role for both the immune system and the gut microbiome in bone and vascular biology. Gut dysbiosis, compromised gut epithelial barrier and immune cell dysfunction are prominent features of the uraemic milieu. These alterations might contribute to the inflammatory state observed in CKD and could have a central role in the pathogenesis of CKD-MBD. The emerging fields of osteoimmunology and osteomicrobiology add another level of complexity to the pathogenesis of CKD-MBD, but also create novel therapeutic opportunities.
Topics: Humans; Chronic Kidney Disease-Mineral and Bone Disorder; Dysbiosis; Quality of Life; Renal Insufficiency, Chronic; Inflammation; Parathyroid Hormone
PubMed: 37488276
DOI: 10.1038/s41581-023-00736-7 -
American Journal of Kidney Diseases :... Feb 2024Maintaining normal calcium and phosphate homeostasis is essential for optimal cellular, metabolic, and organ function. Parathyroid hormone, fibroblast growth factor 23,... (Review)
Review
Maintaining normal calcium and phosphate homeostasis is essential for optimal cellular, metabolic, and organ function. Parathyroid hormone, fibroblast growth factor 23, and 1,25-dihydroxyvitamin D regulate calcium and phosphate homeostasis via multiple interlinked feedback loops, receptors, ion channels, and transporters. Following an initial overview of the stimuli and effects of the different hormonal regulators, this installment of AJKD's Core Curriculum in Nephrology reviews the physiology and pathophysiology of calcium and phosphate disorders through the lens of a series of illustrative cases. The cases span clinical conundrums commonly encountered by nephrologists in their daily clinical practice and other less common disorders. Some of the cases present in the outpatient clinic setting and others in the inpatient hospital setting. Patients with normal kidney function, chronic kidney disease, kidney failure, and acute kidney injury are all represented. Some of the disorders are iatrogenic, and some are due to native disease. All demonstrate key aspects of pathophysiology that are essential knowledge for nephrology clinicians of all career stages.
Topics: Humans; Calcium; Phosphates; Parathyroid Hormone; Renal Insufficiency, Chronic; Curriculum; Fibroblast Growth Factors
PubMed: 38099870
DOI: 10.1053/j.ajkd.2023.04.017 -
Hepatology (Baltimore, Md.) Dec 2023Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role...
BACKGROUND AND AIMS
Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of HSCs and hepatic fibrosis was examined.
APPROACH AND RESULTS
PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl 4 )-treated or methionine and choline-deficient diet (MCD)-fed C57/BL6 mice. The mRNA level of hepatic PTH1R was positively correlated to α-smooth muscle actin in patients with liver cirrhosis. Mice with HSCs-specific PTH1R deletion were protected from CCl 4 , MCD, or western diet, plus low-dose CCl 4 -induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl 4 -treated mice. Mouse primary HSCs and LX2 cell lines were used for in vitro experiments. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with mRNA sequencing in HSCs revealed that cAMP response element-binding protein-like 2 (Crebl2), a novel regulator in HSCs treated by PTH that interacted with mothers against decapentaplegic homolog 3 (SMAD3) and increased the transcription of TGFβ in activating HSCs and collagen deposition. In agreement, HSCs-specific Crebl2 deletion ameliorated PTH-induced liver fibrosis in CCl 4 -treated mice.
CONCLUSIONS
In both mouse and human models, we found that PTH1R was highly expressed in activated HSCs and fibrotic liver. PTH1R signaling regulated collagen production in the HSCs through Crebl2/SMAD3/TGFβ regulatory circuits. Blockade of PTH1R signaling in HSCs might help mitigate the development of liver fibrosis.
Topics: Humans; Mice; Animals; Receptor, Parathyroid Hormone, Type 1; Cyclic AMP Response Element-Binding Protein; Liver Cirrhosis; Collagen; Transforming Growth Factor beta; RNA, Messenger
PubMed: 36939197
DOI: 10.1097/HEP.0000000000000333 -
Best Practice & Research. Clinical... Mar 2024After identification of fibroblast growth factor (FGF) 23 as the pivotal regulator of chronic serum inorganic phosphate (Pi) levels, the etiology of disorders causing... (Review)
Review
After identification of fibroblast growth factor (FGF) 23 as the pivotal regulator of chronic serum inorganic phosphate (Pi) levels, the etiology of disorders causing hypophosphatemic rickets/osteomalacia has been clarified, and measurement of intact FGF23 serves as a potent tool for differential diagnosis of chronic hypophosphatemia. Additionally, measurement of bone-specific alkaline phosphatase (BAP) is recommended to differentiate acute and subacute hypophosphatemia from chronic hypophosphatemia. This article divides the etiology of chronic hypophosphatemia into 4 groups: A. FGF23 related, B. primary tubular dysfunction, C. disturbance of vitamin D metabolism, and D. parathyroid hormone 1 receptor (PTH1R) mediated. Each group is further divided into its inherited form and acquired form. Topics for each group are described, including "ectopic FGF23 syndrome," "alcohol consumption-induced FGF23-related hypophosphatemia," "anti-mitochondrial antibody associated hypophosphatemia," and "vitamin D-dependent rickets type 3." Finally, a flowchart for differential diagnosis of chronic hypophosphatemia is introduced.
Topics: Humans; Hypophosphatemia; Familial Hypophosphatemic Rickets; Phosphates; Fibroblast Growth Factors; Osteomalacia; Vitamin D
PubMed: 38087658
DOI: 10.1016/j.beem.2023.101851 -
Nature Sep 2023Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets....
Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets. Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development. Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (G) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with G. The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications.
Topics: Humans; Arrestin; Binding Sites; GTP-Binding Protein alpha Subunits, Gs; Imidazolidines; Ligands; Peptides; Protein Conformation; Receptor, Parathyroid Hormone, Type 1; Receptors, G-Protein-Coupled; Signal Transduction; Spiro Compounds; Drug Design
PubMed: 37524305
DOI: 10.1038/s41586-023-06467-w -
Science Translational Medicine Nov 2023Low back pain (LBP) is one of the most prevalent diseases affecting quality of life, with no disease-modifying therapy. During aging and spinal degeneration, the balance...
Low back pain (LBP) is one of the most prevalent diseases affecting quality of life, with no disease-modifying therapy. During aging and spinal degeneration, the balance between the normal endplate (EP) bilayers of cartilage and bone shifts to more bone. The aged/degenerated bony EP has increased porosity because of osteoclastic remodeling activity and may be a source of LBP due to aberrant sensory innervation within the pores. We used two mouse models of spinal degeneration to show that parathyroid hormone (PTH) treatment induced osteogenesis and angiogenesis and reduced the porosity of bony EPs. PTH increased the cartilaginous volume and improved the mechanical properties of EPs, which was accompanied by a reduction of the inflammatory factors cyclooxygenase-2 and prostaglandin E. PTH treatment furthermore partially reversed the innervation of porous EPs and reversed LBP-related behaviors. Conditional knockout of PTH 1 receptors in the nucleus pulposus (NP) did not abolish the treatment effects of PTH, suggesting that the NP is not the primary source of LBP in our mouse models. Last, we showed that aged rhesus macaques with spontaneous spinal degeneration also had decreased EP porosity and sensory innervation when treated with PTH, demonstrating a similar mechanism of PTH action on EP sclerosis between mice and macaques. In summary, our results suggest that PTH treatment could partially reverse EP restructuring during spinal regeneration and support further investigation into this potentially disease-modifying treatment strategy for LBP.
Topics: Mice; Animals; Parathyroid Hormone; Low Back Pain; Macaca mulatta; Quality of Life; Disease Models, Animal
PubMed: 37967203
DOI: 10.1126/scitranslmed.adg8982 -
Otolaryngologic Clinics of North America Feb 2024Secondary hyperparathyroidism (SHPT) does not initiate as a primary dysfunction of parathyroid glands resulting from an intrinsic defect or disease but is the... (Review)
Review
Secondary hyperparathyroidism (SHPT) does not initiate as a primary dysfunction of parathyroid glands resulting from an intrinsic defect or disease but is the physiologic response of parathyroids to metabolic changes elsewhere in the body occurring over time. SHPT is a manifestation of a chronic condition that classically occurs from chronic kidney disease. In fact, given the relatively recent transition of populations from outside (agrarian) to indoor (industrial, information technology, and so forth) employment and a consequent reduction in sun exposure, combined with diets of highly processed food, vitamin D and calcium deficiencies are now the leading causes of SHPT.
Topics: Humans; Parathyroid Hormone; Hyperparathyroidism, Secondary; Parathyroid Glands; Vitamin D; Vitamins
PubMed: 37634982
DOI: 10.1016/j.otc.2023.07.010 -
Best Practice & Research. Clinical... Jan 2024Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women with hypercalcemia and parathyroid hormone... (Review)
Review
Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women with hypercalcemia and parathyroid hormone (PTH) levels that are either frankly elevated or inappropriately normal. The clinical presentation of PHPT includes three phenotypes: target organ involvement of the renal and skeletal systems; mild asymptomatic hypercalcemia; and more recently, high PTH levels in the context of persistently normal albumin-corrected and ionized serum calcium values. The factors that determine which of these three clinical presentations is more likely to predominate in a given country include the extent to which biochemical screening is employed, the prevalence of vitamin D deficiency, and whether a medical center or practitioner tends to routinely measure PTH levels in the evaluation of low bone density or frank osteoporosis. When biochemical screening is common, asymptomatic primary hyperparathyroidism is the most likely form of the disease. In countries where vitamin D deficiency is prevalent and biochemical screening is not a feature of the health care system, symptomatic disease with skeletal abnormalities is likely to predominate. Finally, when PTH levels are part of the evaluation for low bone mass, the normocalcemic variant is seen. Guidelines for surgical removal of hyperfunctioning parathyroid tissue apply to all three clinical forms of the disease. If guidelines for surgery are not met, parathyroidectomy can also be an appropriate option if there are no medical contraindications to surgery. In settings where either the serum calcium or bone mineral density is of concern, and surgery is not an option, pharmacological approaches are available and effective. Referencing in this article the most current published articles, we review the different presentations of PHPT, with particular emphasis on recent advances in our understanding of target organ involvement and management.
Topics: Humans; Female; Calcium; Hypercalcemia; Hyperparathyroidism, Primary; Osteoporosis; Parathyroid Hormone; Vitamin D Deficiency
PubMed: 30477754
DOI: 10.1016/j.beem.2018.09.013