Parathyroid hormone (PTH) down-regulates PTH/PTH-related protein receptor gene expression in UMR-106 osteoblast-like cells via a 3',5'-cyclic adenosine monophosphate-dependent, protein kinase A-independent pathway

Kawane, Tetsuya; Mimura, Junsei; Yanagawa, Tetsuo; Fujii‐Kuriyama, Yoshiaki; Horiuchi, Noboru

doi:10.1677/joe.0.1780247

Cited by 28 publications

(25 citation statements)

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“…Inasmuch as both NP and AF cells are found to express PTH1R, the observed effects of PTH are very likely due to PTH binding and activation of PTH1R on these cells. Interestingly, expression of PTH1R is not significantly altered by treatment with PTH, over 48 h. However, the expression of PTH1R was previously shown to be downregulated by PTHrP in vascular smooth muscle cells (Song et al, 2009) and by PTH in UMR-106 osteoblast like cells (Kawane et al, 2003). These differences between earlier studies and our present observations can be due to different cell types.…”

Section: Discussioncontrasting

confidence: 91%

“…The action of PTH is also concentration dependent, showing catabolic effects at higher concentrations and anabolic effects at lower concentrations (Swarthout et al, 2002). PTH action on its target cells is initiated by binding to its receptor, PTH1R, which is a G-protein-coupled receptor (GPCR) 269 www.ecmjournal.org P Madiraju et al Parathyroid hormone suppresses disc calcification (Swarthout et al, 2002;Kawane et al, 2003). Activation of PTH1R by PTH leads to the formation of cyclic AMP via the Gαs-mediated stimulation of adenylate cyclase (Swarthout et al, 2002;Kawane et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…PTH action on its target cells is initiated by binding to its receptor, PTH1R, which is a G-protein-coupled receptor (GPCR) 269 www.ecmjournal.org P Madiraju et al Parathyroid hormone suppresses disc calcification (Swarthout et al, 2002;Kawane et al, 2003). Activation of PTH1R by PTH leads to the formation of cyclic AMP via the Gαs-mediated stimulation of adenylate cyclase (Swarthout et al, 2002;Kawane et al, 2003). This leads to the activation of protein kinase A and its downstream signalling.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells

Madiraju

Gawri²,

Wang³

et al. 2013

eCM

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In degenerative intervertebral discs (IVD), type X collagen (COL X) expression (associated with hypertrophic differentiation) and calcification has been demonstrated. Suppression of COL X expression and calcification during disc degeneration can be therapeutic. In the present study we investigated the potential of human parathyroid hormone 1-34 (PTH) in suppressing indicators of calcification potential (alkaline phosphatase (ALP), Ca 2+ , inorganic phosphate (Pi)), and COL X expression. Further, we sought to elucidate the mechanism of PTH action in annulus fibrosus (AF) and nucleus pulposus (NP) cells from human lumbar IVDs with moderate to advanced degeneration. Mitogen activated protein kinase (MAPK) signalling and alterations in the markers of calcification potential were analysed. PTH increased type II collagen (COL II) expression in AF (~200 %) and NP cells (~163 %) and decreased COL X levels both in AF and NP cells (~75 %). These changes in the expression of collagens were preceded by MAPK phosphorylation, which was increased in both AF and NP cells by PTH after 30 min. MAPK signalling inhibitor U0126 and protein kinase-A inhibitor H-89 DCH attenuated PTH stimulated COL II expression in both cell types. PTH decreased ALP activity and increased Ca 2+ release only in NP cells. The present study demonstrates that PTH can potentially retard IVD degeneration by stimulating matrix synthesis and suppressing markers of calcification potential in degenerated disc cells via both MAPK and PKA signalling pathways. Inhibition of further mineral deposition may therefore be a viable therapeutic option for improving the status of degenerating discs.

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Section: Discussioncontrasting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells

Madiraju

Gawri²,

Wang³

et al. 2013

eCM

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“…Binding of PTH or PTHrp to PTH1R results in a very complex signaling pathway activation that includes not only activation of adenylyl cyclase and phospholipase C (PLC) beta (23), but also activation of PLA2 (9), increase in intracellular calcium, activation of PI3 kinase, and mitogen-activated protein kinases ERK1/2 (10,18). The NHE3 promoter response to PTH was analyzed in the presence of either PKA (KT 5720) or PKC (GF109203X) inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms underlying the long-term regulation of NHE3 by parathyroid hormone

Bezerra¹,

Girardi²,

Carraro‐Lacroix³

et al. 2008

American Journal of Physiology-Renal Physiology

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Bezerra CN, Girardi AC, Carraro-Lacroix LR, Rebouças NA. Mechanisms underlying the long-term regulation of NHE3 by parathyroid hormone. Am J Physiol Renal Physiol 294: F1232-F1237, 2008. First published March 5, 2008 doi:10.1152/ajprenal.00025.2007The activity of the Na ϩ /H ϩ exchanger NHE3 is regulated by a number of factors including parathyroid hormone (PTH). In the current study, we used a renal epithelial cell line, the opossum kidney (OKP) cell, to elucidate the mechanisms underlying the long-term effects of PTH on NHE3 transport activity and expression. We observed that NHE3 activity was reduced 6 h after addition of PTH, and this reduction persisted almost unaltered after 24 h. The decrease in activity was associated with diminished NHE3 cell surface expression at 6, 16, and 24 h after PTH addition, total cellular NHE3 protein at 16 and 24 h, and NHE3 mRNA abundance at 24 h. The lower levels of NHE3 mRNA were associated to a small, but significant, decrease in mRNA stability. Additionally, by analyzing the rat NHE3 gene promoter activity in OKP cells, we verified that the regulatory region spanning the segment Ϫ152 to ϩ55 was mildly reduced under the influence of PTH. This effect was completely abolished by the presence of the PKA inhibitor KT 5720. In conclusion, long-term exposure to PTH results in reduction of NHE3 mRNA levels due to a PKA-dependent inhibitory effect on the NHE3 promoter and a small reduction of mRNA half-life, and decrease in the total amount of protein which is preceded by endocytosis of the apical surface NHE3. The decreased NHE3 expression is likely to be responsible for the reduction of sodium, bicarbonate, and fluid reabsorption in the proximal tubule consistently perceived in experimental models of PTH disorders. Naϩ /H ϩ exchange; proximal tubule; hyperparathyroidism; surface expression; promoter activity THE HUMAN BODY has a remarkable ability to maintain precise control of its acid-base and volume status. Although multiple mechanisms throughout the body contribute to this process, the renal proximal tubule plays a fundamental role, since it is responsible for reabsorption of the majority of the filtered sodium, bicarbonate, chloride, and water. Two-thirds of the transcellular NaHCO 3 reabsorption are mediated by proton secretion through the apical membrane Na ϩ /H ϩ exchanger, NHE3 (4, 21), and most of NaCl reabsorption is indirectly related to it. This transporter thereby plays an important role in the maintenance of fluid, electrolyte, and acid-base balance, and its activity is regulated in response to a wide variety of acute and chronic changes in physiological parameters (29,(31)(32)(33).The kidney is one of the major target organs for parathyroid hormone (PTH). PTH, the primary regulator of serum calcium and phosphate homeostasis, acts on the proximal tubule, the thick ascending limb, and the distal convoluted tubule to alter urinary electrolyte and fluid excretion (1,2,7,14,15,17). PTH has a potent inhibitory effect on NHE3. The acute inhibition of NHE3 by PTH has be...

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“…Furthermore, a number of studies have suggested that cAMP/PKA signaling is activated by PTH (1-34) during osteogenic differentiation (8,9,21). However, precisely how the intermittent administration of PTH (1-34) regulates osteogenic differentiation of BMSCs via the cAMP/PKA signaling pathway requires elucidation.…”

Section: Discussionmentioning

confidence: 99%

Intermittent parathyroid hormone (1–34) application regulates cAMP-response element binding protein activity to promote the proliferation and osteogenic differentiation of bone mesenchymal stromal cells, via the cAMP/PKA signaling pathway

Chen

Lin

Yang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The potential effects of intermittent parathyroid hormone (1-34) ] administration on bone formation have previously been investigated. A number of studies have suggested that the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway is associated with PTH-induced osteogenic differentiation. However, the precise signaling pathways and molecular mechanism by which PTH (1-34) induces the osteogenic differentiation of bone mesenchymal stromal cells (BMSCs) remain elusive. The purpose of the present study was to investigate the mechanism underlying the effect of intermittent PTH (1-34) application on the proliferation and osteogenic differentiation of BMSCs. BMSCs were randomly divided into four groups, as follows: Osteogenic medium (control group); osteogenic medium and intermittent PTH (1-34); osteogenic medium and intermittent PTH (1-34) plus the adenylyl cyclase activator forskolin; and osteogenic medium and intermittent PTH (1-34) plus the PKA inhibitor H-89. A cell proliferation assay revealed that PTH (1-34) stimulates BMSC proliferation via the cAMP/PKA pathway. Furthermore, reverse transcription-quantitative polymerase chain reaction, alkaline phosphatase activity testing and cell examination using Alizarin Red S staining demonstrated that PTH (1-34) administration promotes osteogenic differentiation and mineralization, mediated by the cAMP/PKA pathway. Crucially, the results of western blot analyses suggested that PTH (1-34) treatment and, to a greater degree, PTH (1-34) plus forskolin treatment caused an increase in phosphorylated cAMP response element binding protein (p-CREB) expression, but the effect of PTH on p-CREB expression was blocked by H-89. In conclusion, the current study demonstrated that intermittent PTH (1-34) administration regulates downstream proteins, particularly p-CREB, in the cAMP/PKA signaling pathway, to enhance the proliferation, osteogenic differentiation and mineralization of BMSCs.

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Parathyroid hormone (PTH) down-regulates PTH/PTH-related protein receptor gene expression in UMR-106 osteoblast-like cells via a 3',5'-cyclic adenosine monophosphate-dependent, protein kinase A-independent pathway

Cited by 28 publications

References 42 publications

Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells

Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells

Mechanisms underlying the long-term regulation of NHE3 by parathyroid hormone

Intermittent parathyroid hormone (1–34) application regulates cAMP-response element binding protein activity to promote the proliferation and osteogenic differentiation of bone mesenchymal stromal cells, via the cAMP/PKA signaling pathway

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