2 edition of Modulation of parathyroid hormone receptor signal transduction pathways in osteoblasts. found in the catalog.
Modulation of parathyroid hormone receptor signal transduction pathways in osteoblasts.
Written in English
Parathyroid hormone (PTH) is one of the major regulators of bone and mineral homeostasis. The effects of PTH on osteoblasts are mediated by binding to PTH1 receptors, which couple to both Gsalpha and Gq/11 alpha to stimulate adenylyl cyclase (AC) and phospholipase C (PLC) signaling pathways, respectively. Glucocorticoid treatment significantly increased the PTH-stimulated PLC response in osteoblasts by up-regulating the G q/11alpha expression. The first goal of my thesis was to determine the mechanism of regulation of Gq/11alpha expression by glucocorticoids in rat osteoblastic UMR 106-01 cells. The results demonstrated that G 11alpha is the major Gq/11alpha subtype expressed in UMR cells and that glucocorticoids significantly increase G11alpha protein expression. This increase is mediated primarily by decreasing the rate of protein degradation but also by increasing gene transcription. Since glucocorticoids have been reported to regulate the expression of a number of genes in osteoblasts, it was important to determine whether increased G 11alpha to could change the PTH responses in osteoblasts independently of glucocorticoids. A transient transfection method with G11alpha cDNA was used specifically to increase G11alpha protein expression in UMR cells. Increasing G11alpha expression alone augmented both basal and PTH-stimulated PLC activity. In addition, PTH-mediated signaling responses downstream of the G11alpha-coupled PLC pathway, including basal expression and PTH-stimulated membrane translocation of protein kinase C (PKC) isoforms as well as expression of matrix metalloproteinase-13 (MMP-13) gene, were up-regulated by increasing G11alpha expression. These effects of increased G11alpha expression in osteoblasts may contribute to glucocorticoid-induced osteoporosis. In addition to glucocorticoids, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is another hormone that modulates PTH responses in osteoblasts. 1,25(OH)2D3 attenuates PTH responses by inhibiting AC activity, but the mechanism of action was not clear. I set out to elucidate the mechanism by which 1,25(OH) 2D3 inhibits PTH-stimulated AC activity in UMR cells. The results indicated that AC VI is the dominant AC subtype expressed in UMR cells and 1,25(OH)2D3 can activate specific PKC isoforms that lead to phosphorylation of AC VI and inhibition of PTH-stimulated AC activity in osteoblasts. Overall, I demonstrate that PTH signal transduction can be altered by several mechanisms in response to two hormones known to affect osteoblast function.
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Collagen integrin receptors appeared to be required in osteoblast differentiation induced by ascorbic acid. 22 Moreover, studies using antisense cDNA showed that focal adhesion kinase is involved in this process. 63 Recent studies 64 suggest that collagen matrix synthesis in response to ascorbate is a necessary component of the osteoblast Cited by: Studies on parathyroid hormone receptor (PTHrP) and PTH/PTHrP receptor-ablated mice, and in transgenic animals overexpressing PTHrP in the growth plate, have predicted that human disorders caused by mutations in either of these two proteins would be associated with severe abnormalities in endochondral bone formation and in the regulation of mineral ion homeostasis. These insights from genetically manipulated animals have led to the identification of activating and inactivating PTH.
Mice deficient in the parathyroid hormone related receptor, PTHR1, demonstrate premature maturation of chondrocytes and accelerated bone formation, while mice expressing an activated receptor demonstrate decelerated conversion of proliferative chondrocytes into hypertrophic, with a prolonged presence of hypertrophic chondrocytes with delay of vascular invasion (Fig. ). In both cases there is an expected alteration in the proportion of cells in the hypertrophic zone. Osteoblasts Osteoclasts Mechanism of Action of PTH The P'P Receptor 1.U. PTH Receptor Signal Transduction: Overview Second Messengers Cyclic- AMP Calcium PLC Pathway Calcium Channels Na-H Antiporters Modulation of the Adenylyl Cyclase Pathway Gi/Go Modulate Cellular Growth in Some Ce11 Types Author: Linnia H. Mayeenuddin.
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Parathyroid hormone (PTH) was shown to cause a fold increase in the steady-state levels of bone sialoprotein mRNAs within primary cultures of embryonic osteoblasts. The induction could be mimicked by both forskolin and phorbol myristate acetate and was not inhibited by.
Parathyroid hormone (PTH) maintains a physiological balance of calcium and phosphate concentrations by binding to its receptor on the plasma membrane of cells in bone and kidney. It signals through multiple pathways, including protein kinase A (PKA) and protein kinase C (PKC), although a preference for certain pathways is apparent in each organ and by: In mammals, parathyroid hormone (PTH) 1 is the most important hormone affecting bone growth and resorption.
It shares the PTH/PTH-related protein (PTHrP) receptor (PPR) with PTHrP (), the only other known endogenous ligand for PPR.A series of gene disruption studies of PTHrP and/or PPR in mice has indicated that PTH action on PPR can generate either bone-forming or bone-resorbing signaling.
Osteoblasts respond to both fluid shear and parathyroid hormone (PTH) with a rapid increase in intracellular calcium concentration ([Ca 2+] i).Because both stimuli modulate the kinetics of the mechanosensitive cation channel (MSCC), we postulated PTH would enhance the [Ca 2+] i response to fluid shear by increasing the sensitivity of MSCCs.
After a 3‐minute preflow at 1 dyne/cm 2, MC3T3‐E1 Cited by: The parathyroid hormone (PTH) receptor is coupled via guanine nucleotide-binding regulatory proteins (G proteins) to adenylate cyclase and phospholipase C (PLC).
Activation of PLC with the subsequent hydrolysis of phosphatidylinositol 4,5-bisphosphate produces inositol 1,4,5-trisphosphate (IP 3) and diacylglycerol (DAG).Cited by: 2.
At any rate, NMDA receptor channels could participate at least in part in molecular mechanisms underlying regulation of cellular differentiation by CBFA1 through modulation of its gene expression in osteoblasts. Activation of NMDA receptors is shown to result in marked expression of the nuclear transcription factor activator protein-1 (AP1 Cited by: Role of the Parathyroid Hormone Type 1 Receptor (PTH1R) as a Mechanosensor in Osteocyte Survival These novel findings indicate that PTH1R is an important component of mechanical signal transduction in osteocytic MLO‐Y4 cells, and that PTH1R activation by PTHrP‐independent and dependent mechanisms has a relevant role in the prosurvival Cited by: Introduction.
Parathyroid hormone (PTH) is an amino acid peptide hormone synthesized in the chief cells of the parathyroid glands. It is essential for the maintenance of serum calcium concentration within narrow limits through direct actions on bone and kidney, and indirectly through actions on the gastrointestinal tract .PTH also regulates phosphorus metabolism .Cited by: Parathyroid hormone/parathyroid hormone-related protein receptor (PTH/PTHrP type 1 receptor; commonly known as PTHR1) is a family B G-protein-coupled receptor (GPCR) that is expressed primarily in bone, kidney and cartilage but also in other tissues including the vasculature and certain developing organs.
1 PTHR1 couples to several intracellular signalling pathways and transmits stimuli provided by two different naturally occurring polypeptide ligands: PTH Cited by: It functions as a Ca 2+ sensor in the parathyroid and the kidney to detect the Ca 2+ /CaM complexes alter the function of target proteins upon binding and activate a specific calcium signal transduction pathway while the For example, in many cells including osteoblasts, integrin receptor activation after binding to extracellular matrix Cited by: Recent work with the type I parathyroid hormone receptor (PTH 1 R) suggests that biased ligands that selectively activate G-protein-independent arrestin-mediated signalling pathways may hold promise in the treatment of osteoporosis.
Parathyroid hormone (PTH) is a principle regulator of bone and calcium by: Thyroid hormone effects on the target cells are mediated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor (TR) Cited by: Extracellular cations have paradoxical trophic and toxic effects on osteoblast function.
In an effort to explain these divergent actions, we investigated in MC3T3‐E1 osteoblasts if polyvalent cations differentially modulate the agonist‐stimulated cyclic adenosine monophosphate (cAMP) pathway, an important regulator of osteoblastic by: Parathyroid hormone (PTH) is an amino-acid polypeptide hormone functioning as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis.
PTH and PTH-related protein (PTHrP) indirectly activate osteoclasts resulting in increased bone by: Abstract. The parathyroid hormone receptor (PTHR1) mediates the actions of PTH in bone and kidney cells.
The PTHR1 is a seven transmembrane domain-containing, G protein-coupled receptor (GPCR) and is a member of the “family B” subgroup of GPCRs that bind peptide : Thomas J.
Gardella. The parathyroid hormone 1 (PTH1) 1 receptor is a cell-surface signal transducer for PTH and PTH-related protein (PTHrP). PTH plays a central role in calcium homeostasis; the hormone acts on target cells in bone (osteoblasts) and kidney (renal tubule cells) to increase blood calcium levels ().PTHrP is an autocrine factor, believed to be involved in the maintenance of numerous tissues, and.
and parathyroid hormone–related peptide (PTHrP) both signal through the same family B G-protein-coupled-receptor (PTHR1, parathyroid hormone signaling in osteocytes will be PTH receptor signaling via Gsa/cAMP in osteoblast lineage cells is required for iPTH-induced gains in bone by: 8.
ligand with its receptor but do not cause signal transduction. Similar modifications in the parathyroid hormone-related protein (PTHrP) antagonist led to antagonists with increased potency. Further, the partial agonism of this analog could be removed by exchange of residues between PTH and PTHrP.
Studies (39, 40) have found that PTH can increase osteoblast number by reducing the activity of an antagonist for the Wnt signal transduction pathway. Suzuki et al. (41) hypothesised that PTH can combine with PTHR on the surface of osteoblasts to activate protein kinase A signalling, indirectly increase Wnt signalling pathways, and stimulate osteoblast proliferation and Cited by: 4.
Control of osteoblast function and regulation of bone mass. Injectable parathyroid hormone the LRP5 signal transduction pathways were not known to control bone by:. Parathyroid Hormone-Related Protein. A second member of the parathyroid hormone family, parathyroid hormone-related protein (PTHrP), is quite similar to PTH in amino acid sequence and protein structure.
Like PTH, it activates the parathyroid hormone receptor causing increased bone resorption and renal tubular calcium reabsorption. Increased serum concentrations of parathyroid hormone-related .Parathyroid hormone (PTH) down-regulates PTH/PTH-related protein receptor gene expression in UMR osteoblast-like cells via a 3',5'-cyclic adenosine monophosphate-dependent, protein .The receptor links to several G-proteins, including G i, G q/11 and G 12/13, and, in turn, multiple intracellular signaling pathways – activating phospholipases A 2, C and D, and several mitogen-activated protein kinases (MAPKs) [i.e.
extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-jun N-terminal kinase (JNK)], and inhibiting.