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Regulation of Bone Mineral Homeostasis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 41311

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Prof. Dr. Patrick C. D'Haese

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Guest Editor

Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium
Interests: mineral homeostasis; renal osteodystrophy; chronic/acute renal failure

Prof. Anja Verhulst

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Guest Editor

Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2000 Antwerpen, Belgium
Interests: chronic kidney disease; renal diseases

Special Issue Information

Dear colleagues,

Strictly spoken, regulation of bone mineral homeostasis involves the maintenance of the intra- and extracellular levels of calcium and phosphate within a relatively narrow range primarily involving the skeleton, intestine, and kidneys and is achieved through the interplay of three hormones, i.e., parathyroid hormone, the active metabolite of vitamin D 1,25 dihydroxyvitamin D, and fibroblast growth factor 23 (FGF23). Hormonal regulation of bone mineral homeostasis is, however, much more complex and requires the involvement of additional endocrine regulators, such as the sex hormones estrogen and testosterone as well as insulin, cortisol, adipocyte hormones, calcitonin, prolactin, glucocorticoid hormones, and a large number of cytokines. In addition, it becomes more and more apparent that a seemingly endless list of proteins, often categorized as growth factors, such as insulin growth factors, fibroblast growth factors (others than FGF23), epidermal growth factors, transforming growth factor-β, bone morphogenetic proteins, and sclerostin and DKK1 as inhibitors of the Wnt/β-catenin signaling pathway also play significant roles in physiological bone remodeling. Finally, the involvement of other factors in calcium-phosphate handling such as pH, sodium, potassium, magnesium, fluoride, bicarbonate, and sulfate should be recognized. All these factors may be dysregulated in particular disease states like chronic kidney disease and diabetes, genetic disorders, and aging and are targeted using appropriate therapeutics.

Prof. Patrick C. D'Haese
Prof. Anja Verhulst
Guest Editors

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Keywords

Renal osteodystrophy
Hormonal mineral regulation
Phosphate homeostasis
Calcium homeostasis
Bone–kidney axis
Bone metabolism
Vitamin D
Parathyroid hormone

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Published Papers (9 papers)

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Research

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14 pages, 1334 KiB

Open AccessArticle

Lanthionine, a Novel Uremic Toxin, in the Vascular Calcification of Chronic Kidney Disease: The Role of Proinflammatory Cytokines

by Alessandra Fortunata Perna, Luigi Russo, Vittoria D’Esposito, Pietro Formisano, Dario Bruzzese, Carmela Vigorito, Annapaola Coppola, Patrizia Lombari, Domenico Russo and Diego Ingrosso

Int. J. Mol. Sci. 2021, 22(13), 6875; https://doi.org/10.3390/ijms22136875 - 26 Jun 2021

Cited by 11 | Viewed by 2680

Abstract

Vascular calcification (VC) is a risk factor for cardiovascular events and mortality in chronic kidney disease (CKD). Several components influence the occurrence of VC, among which inflammation. A novel uremic toxin, lanthionine, was shown to increase intracellular calcium in endothelial cells and may have a role in VC. A group of CKD patients was selected and divided into patients with a glomerular filtration rate (GFR) of <45 mL/min/1.73 m² and ≥45 mL/min/1.73 m². Total Calcium Score (TCS), based on the Agatston score, was assessed as circulating lanthionine and a panel of different cytokines. A hemodialysis patient group was also considered. Lanthionine was elevated in CKD patients, and levels increased significantly in hemodialysis patients with respect to the two CKD groups; in addition, lanthionine increased along with the increase in TCS, starting from one up to three. Interleukin IL-6, IL-8, and Eotaxin were significantly increased in patients with GFR < 45 mL/min/1.73 m² with respect to those with GFR ≥ 45 mL/min/1.73 m². IL-1b, IL-7, IL-8, IL-12, Eotaxin, and VEGF increased in calcified patients with respect to the non-calcified. IL-8 and Eotaxin were elevated both in the low GFR group and in the calcified group. We propose that lanthionine, but also IL-8 and Eotaxin, in particular, are a key feature of VC of CKD, with possible marker significance. Full article

(This article belongs to the Special Issue Regulation of Bone Mineral Homeostasis)

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18 pages, 7152 KiB

Open AccessArticle

Paracrine Kynurenic Pathway Activation in the Bone of Young Uremic Rats Can Antagonize Anabolic Effects of PTH on Bone Turnover and Strength through the Disruption of PTH-Dependent Molecular Signaling

by Krystyna Pawlak, Beata Sieklucka and Dariusz Pawlak

Int. J. Mol. Sci. 2021, 22(12), 6563; https://doi.org/10.3390/ijms22126563 - 18 Jun 2021

Cited by 5 | Viewed by 2025

Abstract

Secondary hyperparathyroidism and abnormalities in tryptophan (TRP) metabolism are commonly observed in chronic kidney disease (CKD). The present study aimed to establish potential interactions between endogenous parathyroid hormone (PTH) and activation of the bone kynurenine (KYN) pathway in relation to bone turnover and strength in young rats after one month (CKD-1) and three months (CKD-3) of experimental CKD. TRP, KYN, KYN/TRP ratio and bone turnover markers (BTMs) were measured in trabecular and cortical bone tissue. Expression of aryl hydrocarbon receptor (AhR) and the genes involved in osteogenesis was determined in femoral bone. Biomechanical testing of femoral diaphysis and femoral neck was also performed. Activation of the KYN pathway in trabecular bone during CKD development intensified the expression of genes related to osteogenesis, which led to a decrease in cyclic adenosine monophosphate (cAMP) and BTMs levels, resulting in a stiffer and mechanically weaker femoral neck. In contrast, reduction of the KYN pathway in cortical bone allowed to unblock the PTH-dependent anabolic activating transcription factor 4/parathyroid hormone 1 receptor (PTH1R/ATF4) axis, led to cAMP accumulation, better bone turnover and strength in the course of CKD development. In summary, the paracrine KYN pathway in bone can interfere with the anabolic effects of PTH on bone through disrupting PTH-dependent molecular signaling. Full article

(This article belongs to the Special Issue Regulation of Bone Mineral Homeostasis)

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18 pages, 1679 KiB

Open AccessArticle

Recombinant IGF-1 Induces Sex-Specific Changes in Bone Composition and Remodeling in Adult Mice with Pappa2 Deficiency

by Leticia Rubio, Antonio Vargas, Patricia Rivera, Antonio J. López-Gambero, Rubén Tovar, Julian K. Christians, Stella Martín-de-las-Heras, Fernando Rodríguez de Fonseca, Julie A. Chowen, Jesús Argente and Juan Suárez

Int. J. Mol. Sci. 2021, 22(8), 4048; https://doi.org/10.3390/ijms22084048 - 14 Apr 2021

Cited by 11 | Viewed by 3137

Abstract

Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive Pappa2 knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. Pappa2^ko/ko mice (both sexes) had reduced body and bone length. Male Pappa2^ko/ko mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in Igfbp3, osteopontin (resorption) and osteocalcin (formation) characterized the bone of Pappa2^ko/ko females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in Pappa2^ko/ko mice (both sexes). rmIGF-1 treatment in Pappa2^ko/ko females also increased collagen maturity, and Igfbp3, Igfbp5, Col1a1 and osteopontin expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with Pappa2 deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair. Full article

(This article belongs to the Special Issue Regulation of Bone Mineral Homeostasis)

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14 pages, 10508 KiB

Open AccessArticle

Glucocorticoid Receptor Regulates TNFSF11 Transcription by Binding to Glucocorticoid Responsive Element in TNFSF11 Proximal Promoter Region

by Nika Lovšin and Janja Marc

Int. J. Mol. Sci. 2021, 22(3), 1054; https://doi.org/10.3390/ijms22031054 - 21 Jan 2021

Cited by 8 | Viewed by 2842

Abstract

Glucocorticoid osteoporosis is a serious side effect of long term glucocorticoid uptake and it is caused by osteoblast apoptosis and imbalance in the major bone remodeling pathway RANK/RANKL/OPG. The impact of glucocorticoid on the maintenance of RANK/RANKL/OPG is well explored; dexamethasone was shown to disturb the ratio between OPG and RANKL level by decreasing the expression level of OPG and increasing level of RANKL. Here, were aimed to decipher whether glucocorticoid receptor directly influences RANKL promoter activity and its transcriptional regulation. We demonstrate that overexpression of glucocorticoid receptor (GR) NR3C1 increased RANKL promoter activity in human osteosarcoma, cervical cancer (2-fold) and adenocarcinoma cells (4.5-fold). Mutational analysis revealed that +352 site in the RANKL promoter is functional glucocorticoid responsive element (GRE) since the effect of GR on RANKL promoter activity was diminished by mutation at this site. Overexpression of NR3C1 upregulated RANKL mRNA expression 1.5-fold in human A549 and HOS cells. On the other hand silencing of NR3C1 caused slight decrease in RANKL mRNA level, suggesting that NR3C1 directly accounts for RANKL transcriptional regulation. Using electrophoretic mobility shift assay we demonstrate that NR3C1 binds to the proximal RANKL promoter region. Our study provides evidences that NR3C1 directly upregulates RANKL transcription in human cell lines and connects the missing link in the mechanism of RANK/RANKL/OPG imbalance of glucocorticoid induced osteoporosis. Full article

(This article belongs to the Special Issue Regulation of Bone Mineral Homeostasis)

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14 pages, 3463 KiB

Open AccessArticle

Parthenolide Has Negative Effects on In Vitro Enhanced Osteogenic Phenotypes by Inflammatory Cytokine TNF-α via Inhibiting JNK Signaling

by Jin-Ho Park, Young-Hoon Kang, Sun-Chul Hwang, Se Heang Oh and June-Ho Byun

Int. J. Mol. Sci. 2020, 21(15), 5433; https://doi.org/10.3390/ijms21155433 - 30 Jul 2020

Cited by 6 | Viewed by 2525

Abstract

Nuclear factor kappa B (NF-κB) regulates inflammatory gene expression and represents a likely target for novel disease treatment approaches, including skeletal disorders. Several plant-derived sesquiterpene lactones can inhibit the activation of NF-κB. Parthenolide (PTL) is an abundant sesquiterpene lactone, found in Mexican Indian Asteraceae family plants, with reported anti-inflammatory activity, through the inhibition of a common step in the NF-κB activation pathway. This study examined the effects of PTL on the enhanced, in vitro, osteogenic phenotypes of human periosteum-derived cells (hPDCs), mediated by the inflammatory cytokine tumor necrosis factor (TNF)-α. PTL had no significant effects on hPDC viability or osteoblastic activities, whereas TNF-α had positive effects on the in vitro osteoblastic differentiation of hPDCs. c-Jun N-terminal kinase (JNK) signaling played an important role in the enhanced osteoblastic differentiation of TNF-α-treated hPDCs. Treatment with 1 µM PTL did not affect TNF-α-treated hPDCs; however, 5 and 10 µM PTL treatment decreased the histochemical detection and activity of alkaline phosphatase (ALP), alizarin red-positive mineralization, and the expression of ALP and osteocalcin mRNA. JNK phosphorylation decreased significantly in TNF-α-treated hPDCs pretreated with PTL. These results suggested that PTL exerts negative effects on the increased osteoblastic differentiation of TNF-α-treated hPDCs by inhibiting JNK signaling. Full article

(This article belongs to the Special Issue Regulation of Bone Mineral Homeostasis)

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Review

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19 pages, 1320 KiB

Open AccessReview

Fibrosis in Chronic Kidney Disease: Pathogenesis and Consequences

by Sara Panizo, Laura Martínez-Arias, Cristina Alonso-Montes, Pablo Cannata, Beatriz Martín-Carro, José L. Fernández-Martín, Manuel Naves-Díaz, Natalia Carrillo-López and Jorge B. Cannata-Andía

Int. J. Mol. Sci. 2021, 22(1), 408; https://doi.org/10.3390/ijms22010408 - 2 Jan 2021

Cited by 167 | Viewed by 10997

Abstract

Fibrosis is a process characterized by an excessive accumulation of the extracellular matrix as a response to different types of tissue injuries, which leads to organ dysfunction. The process can be initiated by multiple and different stimuli and pathogenic factors which trigger the cascade of reparation converging in molecular signals responsible of initiating and driving fibrosis. Though fibrosis can play a defensive role, in several circumstances at a certain stage, it can progressively become an uncontrolled irreversible and self-maintained process, named pathological fibrosis. Several systems, molecules and responses involved in the pathogenesis of the pathological fibrosis of chronic kidney disease (CKD) will be discussed in this review, putting special attention on inflammation, renin-angiotensin system (RAS), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, microRNAs (miRs), and the vitamin D hormonal system. All of them are key factors of the core and regulatory pathways which drive fibrosis, having a great negative kidney and cardiac impact in CKD. Full article

(This article belongs to the Special Issue Regulation of Bone Mineral Homeostasis)

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28 pages, 1801 KiB

Open AccessReview

Role of Metabolism in Bone Development and Homeostasis

by Akiko Suzuki, Mina Minamide, Chihiro Iwaya, Kenichi Ogata and Junichi Iwata

Int. J. Mol. Sci. 2020, 21(23), 8992; https://doi.org/10.3390/ijms21238992 - 26 Nov 2020

Cited by 59 | Viewed by 6175

Abstract

Carbohydrates, fats, and proteins are the underlying energy sources for animals and are catabolized through specific biochemical cascades involving numerous enzymes. The catabolites and metabolites in these metabolic pathways are crucial for many cellular functions; therefore, an imbalance and/or dysregulation of these pathways causes cellular dysfunction, resulting in various metabolic diseases. Bone, a highly mineralized organ that serves as a skeleton of the body, undergoes continuous active turnover, which is required for the maintenance of healthy bony components through the deposition and resorption of bone matrix and minerals. This highly coordinated event is regulated throughout life by bone cells such as osteoblasts, osteoclasts, and osteocytes, and requires synchronized activities from different metabolic pathways. Here, we aim to provide a comprehensive review of the cellular metabolism involved in bone development and homeostasis, as revealed by mouse genetic studies. Full article

(This article belongs to the Special Issue Regulation of Bone Mineral Homeostasis)

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20 pages, 2705 KiB

Open AccessReview

New Aspects of the Kidney in the Regulation of Fibroblast Growth Factor 23 (FGF23) and Mineral Homeostasis

by Maria L. Mace, Klaus Olgaard and Ewa Lewin

Int. J. Mol. Sci. 2020, 21(22), 8810; https://doi.org/10.3390/ijms21228810 - 20 Nov 2020

Cited by 39 | Viewed by 6193

Abstract

The bone-derived hormone fibroblast growth factor 23 (FGF23) acts in concert with parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol in the regulation of calcium (Ca) and phosphate (P) homeostasis. More factors are being identified to regulate FGF23 levels and the endocrine loops between the three hormones. The present review summarizes the complex regulation of FGF23 and the disturbed FGF23/Klotho system in chronic kidney disease (CKD). In addition to the reduced ability of the injured kidney to regulate plasma levels of FGF23, several CKD-related factors have been shown to stimulate FGF23 production. The high circulating FGF23 levels have detrimental effects on erythropoiesis, the cardio-vascular system and the immune system, all contributing to the disturbed system biology in CKD. Moreover, new factors secreted by the injured kidney and the uremic calcified vasculature play a role in the mineral and bone disorder in CKD and create a vicious pathological crosstalk. Full article

(This article belongs to the Special Issue Regulation of Bone Mineral Homeostasis)

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18 pages, 2283 KiB

Open AccessReview

Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways

by Britt Opdebeeck, Isabel R. Orriss, Ellen Neven, Patrick C. D’Haese and Anja Verhulst

Int. J. Mol. Sci. 2020, 21(20), 7636; https://doi.org/10.3390/ijms21207636 - 15 Oct 2020

Cited by 10 | Viewed by 3246

Abstract

Arterial calcification, the deposition of calcium-phosphate crystals in the extracellular matrix, resembles physiological bone mineralization. It is well-known that extracellular nucleotides regulate bone homeostasis raising an emerging interest in the role of these molecules on arterial calcification. The purinergic independent pathway involves the enzymes ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs), ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), 5′-nucleotidase and alkaline phosphatase. These regulate the production and breakdown of the calcification inhibitor—pyrophosphate and the calcification stimulator—inorganic phosphate, from extracellular nucleotides. Maintaining ecto-nucleotidase activities in a well-defined range is indispensable as enzymatic hyper- and hypo-expression has been linked to arterial calcification. The purinergic signaling dependent pathway focusses on the activation of purinergic receptors (P1, P2X and P2Y) by extracellular nucleotides. These receptors influence arterial calcification by interfering with the key molecular mechanisms underlying this pathology, including the osteogenic switch and apoptosis of vascular cells and possibly, by favoring the phenotypic switch of vascular cells towards an adipogenic phenotype, a recent, novel hypothesis explaining the systemic prevention of arterial calcification. Selective compounds influencing the activity of ecto-nucleotidases and purinergic receptors, have recently been developed to treat arterial calcification. However, adverse side-effects on bone mineralization are possible as these compounds reasonably could interfere with physiological bone mineralization. Full article

(This article belongs to the Special Issue Regulation of Bone Mineral Homeostasis)

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