scholarly journals Physiological and Pharmacological Roles of PTH and PTHrP in Bone Using Their Shared Receptor, PTH1R

2021 ◽  
Author(s):  
T John Martin ◽  
Natalie A Sims ◽  
Ego Seeman
Keyword(s):  
Bone Remodeling ◽  
Calcium Homeostasis ◽  
Physiological Role ◽  
Osteoclast Formation ◽  
Hormonal Control ◽  
Daily Injection ◽  
Bone Lengthening ◽  
Paracrine Factor ◽  
Local Factor ◽  
Amino Terminal

Abstract Parathyroid hormone (PTH) and the paracrine factor, PTH-related protein (PTHrP), have preserved in evolution sufficient identities in their amino-terminal domains to share equivalent actions upon a common G protein-coupled receptor, PTH1R, that predominantly uses the cyclic adenosine monophosphate-protein kinase A signaling pathway. Such a relationship between a hormone and local factor poses questions about how their common receptor mediates pharmacological and physiological actions of the two. Mouse genetic studies show that PTHrP is essential for endochondral bone lengthening in the fetus and is essential for bone remodeling. In contrast, the main postnatal function of PTH is hormonal control of calcium homeostasis, with no evidence that PTHrP contributes. Pharmacologically, amino-terminal PTH and PTHrP peptides (teriparatide and abaloparatide) promote bone formation when administered by intermittent (daily) injection. This anabolic effect is remodeling-based with a lesser contribution from modeling. The apparent lesser potency of PTHrP than PTH peptides as skeletal anabolic agents could be explained by lesser bioavailability to PTH1R. By contrast, prolongation of PTH1R stimulation by excessive dosing or infusion, converts the response to a predominantly resorptive one by stimulating osteoclast formation. Physiologically, locally generated PTHrP is better equipped than the circulating hormone to regulate bone remodeling, which occurs asynchronously at widely distributed sites throughout the skeleton where it is needed to replace old or damaged bone. While it remains possible that PTH, circulating within a narrow concentration range, could contribute in some way to remodeling and modeling, its main physiological role is in regulating calcium homeostasis.

Influence of Angptl1 on Osteoclast Formation and Osteoblastic Phenotype in Mouse Cells.

2020 ◽  
Author(s):  
Masayoshi Ishida ◽  
Naoyuki Kawao ◽  
Yuya Mizukami ◽  
Yoshimasa Takafuji ◽  
Hiroshi Kaji
Keyword(s):  
Bone Remodeling ◽  
Adipogenic Differentiation ◽  
Mouse Cell ◽  
Osteoblastic Differentiation ◽  
Osteoclast Formation ◽  
Bone Morphogenetic Protein 2 ◽  
Raw 264.7 Cells ◽  
Tartrate Resistant Acid Phosphatase ◽  
Peroxisome Proliferator ◽  
Mrna Levels

Abstract Background: Osteoblasts and osteoclasts play important roles during the bone remodeling in the physiological and pathophysiological states. Although angiopoietin family Angiopoietin like proteins (Angptls), including Angptl1, have been reported to be involved in inflammation, lipid metabolism and angiogenesis, the roles of Angptl1 in bone have not been reported so far. Methods: We examined the effects of Angptl1 overexpression on the osteoblast and osteoclast phenotypes using mouse cell lines.Results: Angptl1 overexpression significantly inhibited the osteoclast formation and mRNA levels of tartrate-resistant acid phosphatase and cathepsin K enhanced by receptor activator of nuclear factor κB ligand in RAW 264.7 cells. Moreover, Angptl1 overexpression significantly enhanced Osterix mRNA levels, alkaline phosphatase activity and mineralization induced by bone morphogenetic protein-2 in ST2 cells, although it did not affect the expression of osteogenic genes in MC3T3-E1 cells. On the other hand, Angptl1 overexpression significantly reduced the mRNA levels of peroxisome proliferator-activated receptor γ and adipocyte protein-2 induced by adipogenic medium in 3T3-L1 cells.Conclusions: The present study first indicated that Angptl1 suppresses and enhances osteoclast formation and osteoblastic differentiation in mouse cell line, respectively, although it inhibits adipogenic differentiation of 3T3-L1 cells. These data suggest the possibility that Angptl1 might be physiologically related to bone remodeling.

Bone Biology

2017 ◽  
Author(s):  
Elizabeth Weiss
Keyword(s):  
Trabecular Bone ◽  
Bone Remodeling ◽  
Calcium Homeostasis ◽  
Bone Biology ◽  
Diarthrodial Joint ◽  
Bone Damage ◽  
Bone Changes ◽  
Cartilage Cells ◽  
Wolff’S Law ◽  
Haversian System

This chapter introduces readers to the basics of understanding bone’s functions, which include calcium homeostasis and enabling movement, bone’s components, such as the collagen, and bone’s organization, such as the Haversian system found in cortical bone. The focus of this chapter is on explaining concepts of bone remodeling, which is thought to prevent fractures and other bone damage, and repair, which can take place at macro-levels and micro-levels. Wolff’s Law of bone remodeling, which was initially focused on trabecular bone changes, is discussed in terms of bone’s response to forces that result in strains and stresses. Finally, diarthrodial joint remodeling and repair are discussed; cartilage cells were once thought to be static, yet now they are known to also respond to stresses.

SO039BETA3-ADRENORECEPTOR AS A NEW PLAYER IN SYMPATHETIC REGULATION OF THE ACID-BASE HOMEOSTASIS IN THE KIDNEY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Serena Milano ◽  
Andrea Gerbino ◽  
Monica Carmosino ◽  
Maria Svelto ◽  
Giuseppe Procino
Keyword(s):  
Atpase Activity ◽  
Physiological Role ◽  
Mouse Kidney ◽  
Hormonal Control ◽  
Resting Cells ◽  
Atpase Inhibitor ◽  
Acid Base ◽  
Urine Ph ◽  
Knock Out ◽  
Mouse Urine

Abstract Background and Aims Sympathetic nervous system has a key role in the regulation of renal function. We previously showed that, in mouse, the β3-adrenoreceptor (β3-AR) localizes in most of the nephron segments and its selective agonism promotes a potent antidiuretic effect. Here, we evaluate the expression of β3-AR in kidney intercalated cells (ICs) which are associated with the regulation of acid-base homeostasis in distal segments of the kidney tubule. The aim of this study is to investigate whether the β3-AR might play a role in the acid-base homeostasis operated by the kidney. Method The β3-AR expression in mouse kidney ICs was investigated by confocal microscopy. Wild type (wt) and β3-AR knock-out (ko) mice were used to study the role of β3-AR in the renal acid-base homeostasis. Mouse urine were collected using metabolic cages and pH was measured. Immunofluorescence and Western blotting experiments were performed to evaluate the localization and the abundance of renal H+-ATPase in wt and β3-AR ko mice. Kidney cells expressing human β3-AR (M1-β3-AR) and endogenous H+-ATPase were used to investigate the possible effects of β3-AR stimulation on the activity/localization of H+-ATPase. Live imaging experiments using the pH-sensitive dye BCECF were carried out to determine intracellular pH and assess H+-ATPase activity.  Immunofluorescence experiments were performed to reveal the effects of β3-AR activation on H+-ATPase localization. Results Co-localization study of β3-AR with either H+-ATPase or Cl−/HCO3− exchanger pendrin in mouse kidney showed that β3-AR is expressed in H+-secreting type A, in HCO3— secreting type B, and in non-A non-B ICs. The urine pH of β3-AR ko mice was significantly higher compared with wt mice. In line with these results, localization and expression analysis showed that renal H+-ATPase significantly decreased in β3-AR ko mice compared to wt mice, supporting the idea that H+ secretion is partially blunted in these animals. Of note, exposure of M1-β3-AR cells to a selective β3-AR agonist induced a 2.5 fold increase of H+-ATPase activity compared to resting cells and this effect was prevented by a selective β3-AR antagonist or by the H+-ATPase inhibitor bafilomycin. Moreover, β3-AR agonism enhanced H+-ATPase apical expression in M1-β3-AR cells. In addition, the PKA inhibitor H89 abolished the stimulatory effect of β3-AR agonism, demonstrating the involvement of the cAMP/PKA pathway. Conclusion The present data suggest that modulation of H+-ATPase activity in renal ICs by endogenous β3-AR agonists may play an addition physiological role in hormonal control of renal acid-base homeostasis.

scholarly journals CCR3 deficiency is associated with increased osteoclast activity and reduced cortical bone volume in adult male mice

2020 ◽  
pp. jbc.RA120.015571
Author(s):  
Sara Rosendahl ◽  
Rima Sulniute ◽  
Michaela Eklund ◽  
Cecilia Koskinen Holm ◽  
Marcus J. O. Johansson ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cortical Bone ◽  
Bone Remodeling ◽  
Adult Male ◽  
Chemokine Receptors ◽  
Osteoclast Formation ◽  
Male Mice ◽  
Primary Mouse ◽  
Deficient Mice

Increasing evidence emphasizes the importance of chemokines and chemokine receptors as regulators of bone remodeling. The C-C chemokine receptor 3 (CCR3) is dramatically up-regulated during osteoclastogenesis but the role of CCR3 in osteoclast formation and bone remodeling in adult mice is unknown. Herein, we used bone marrow macrophages (BMM) derived from adult male CCR3-proficient and -deficient mice to study the role of CCR3 in osteoclast formation and activity. CCR3 deficiency was associated with formation of giant hypernucleated osteoclasts, enhanced bone resorption when cultured on bone slices and altered mRNA expression of related chemokine receptors and ligands. Additionally, primary mouse calvarial osteoblasts isolated from CCR3-deficient mice showed increased mRNA expression of the osteoclast activator related gene, receptor activator of nuclear factor kappa-B ligand (Rankl), and osteoblast differentiation associated genes. Micro-computed tomography analyses of femurs from CCR3-deficient mice revealed a bone phenotype that entailed less cortical thickness and volume. Consistent with our in vitro studies, the number of osteoclasts did not differ between the genotypes in vivo. Moreover, an increased endo-cortical osteoid mineralization rate and higher trabecular and cortical bone formation rate was displayed in CCR3-deficient mice. Collectively, our data show that CCR3 deficiency influences osteoblast and osteoclast differentiation and that it is associated with thinner cortical bone in adult male mice.

scholarly journals The Highly Conserved TldD and TldE Proteins of Escherichia coli Are Involved in Microcin B17 Processing and in CcdA Degradation

2002 ◽  
Vol 184 (12) ◽  
pp. 3224-3231 ◽  
Author(s):  
Noureddine Allali ◽  
Hassan Afif ◽  
Martine Couturier ◽  
Laurence Van Melderen
Keyword(s):  
Escherichia Coli ◽  
Topoisomerase Ii ◽  
Resistance Mechanism ◽  
Physiological Role ◽  
Leader Peptide ◽  
Peptide Antibiotic ◽  
Amino Terminal ◽  
Bacterial Mutants ◽  
Microcin B17

ABSTRACT Microcin B17 (MccB17) is a peptide antibiotic produced by Escherichia coli strains carrying the pMccB17 plasmid. MccB17 is synthesized as a precursor containing an amino-terminal leader peptide that is cleaved during maturation. Maturation requires the product of the chromosomal tldE (pmbA) gene. Mature microcin is exported across the cytoplasmic membrane by a dedicated ABC transporter. In sensitive cells, MccB17 targets the essential topoisomerase II DNA gyrase. Independently, tldE as well as tldD mutants were isolated as being resistant to CcdB, another natural poison of gyrase encoded by the ccd poison-antidote system of plasmid F. This led to the idea that TldD and TldE could regulate gyrase function. We present in vivo evidence supporting the hypothesis that TldD and TldE have proteolytic activity. We show that in bacterial mutants devoid of either TldD or TldE activity, the MccB17 precursor accumulates and is not exported. Similarly, in the ccd system, we found that TldD and TldE are involved in CcdA and CcdA41 antidote degradation rather than being involved in the CcdB resistance mechanism. Interestingly, sequence database comparisons revealed that these two proteins have homologues in eubacteria and archaebacteria, suggesting a broader physiological role.

BONE REMODELING MARKERS AS PREDICTORS OF BONE METABOLIC CHANGES IN MALES WITH DIABETIC OSTEOPATHY

2020 ◽  
Vol 58 (3) ◽  
pp. 290-293
Author(s):  
S. S. Safarova ◽  
S. S. Safarova
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Bone Remodeling ◽  
Control Group ◽  
Mineral Density ◽  
Amino Terminal ◽  
Bone Remodeling Markers ◽  
History Of ◽  
Male Patients

Diabetic osteopathy is one of the little studied complications of diabetes mellitus (DM), which leads to common lowtrauma fractures and, as a consequence, disability and death. The level of insulin is connected with bone functional and morphological changes followed by decreased bone mineral density (BMD) in the early stages of diabetic osteopathy. Objective: to study bone morphofunctional properties in males with type 1 and 2 DM (T1DM and T2DM). Subjects and methods. Examinations were made in 41 male patients with T1DM and 52 male patients with T2DM without a history of fractures. Their age varied from 40 to 70 years (mean age, 55.8±0.7 years and 58.4±0.9 years, respectively). A control group consisted of 34 patients (mean age, 55.9±0.9 years) without a history of DM. Patients with other endocrine disorders, end-stage complications, or chronic liver and kidney diseases were excluded from the investigation. BMD was determined by dual-energy X-ray absorptiometry (DXA). Serum bone remodeling markers (procollagen type 1 amino-terminal propeptide and C-terminal telopeptide), as well as 25(OH)D, parathyrin, insulin, glycated hemoglobin (HbA1c), and electrolytes (Ca2+, P+) were evaluated. Results and discussion. An association of BMD with renal function, HbA1c, and body mass index was observed in patients with T2DM. In the T1MD group, BMD was closely related to insulin deficiency and was significantly lower than that in the control group. In patients with vitamin D deficiency, BMD was significantly lower than in those with normal vitamin D levels (p<0.05). The patients with T1DM displayed both a decrease in BMD (p<0.05) and a pronounced change in the levels of bone markers (p<0.05). Those with T2DM had impaired bone remodeling processes, which was determined by the level of these markers (p<0.05) and observed in the presence of normal BMD due to the complex pathophysiology of the underlying disease. Conclusion. Vitamin D deficiency, insufficient and decreased insulin sensitivity, hyperglycemia, and overweight are important causes of osteopathy in patients with DM. The markers of bone remodeling may become promising indicators for diagnosing osteopathy, but additional studies are needed to elaborate recommendations for their use in routine practice in order to predict and prevent this complication of DM.

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