Parathyroid hormone and prostaglandin E2 stimulate both inositol phosphates and cyclic AMP accumulation in mouse osteoblast cultures

Farndale, Richard W.; Sandy, Jonathan R; Atkinson, Susan J.; Meghji, S; Meikle, Murray C.

doi:10.1042/bj2520263

Cited by 97 publications

(30 citation statements)

References 33 publications

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“…We have shown that the mitogenic effect of PTH is mimicked in osteoblast-like cells [12] by phospholipase C treatment or by protein kinase C activation by phorbol ester, which implicated phosphoinositide turnover in the pathway of PTH action, as confirmed directly in more recent work [15]. Moreover, we have also shown that, in chicken sternum chondroblasts, the central region of the PTH molecule is sufficient to stimulate thymidine incorporation into DNA [16].…”

Section: Introductionsupporting

confidence: 52%

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Stimulation by defined parathyroid hormone fragments of cell proliferation in skeletal-derived cell cultures

Sömjen¹,

Binderman

Schlüter

et al. 1990

Biochemical Journal

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We have reported previously that parathyroid hormone (PTH) acts on cultured bone cells to stimulate creatine kinase (CK) activity and [3H]thymidine incorporation into DNA via phosphoinositide turnover, in addition to its other actions via increased cyclic AMP production. We also found that mid-region fragments of PTH stimulate [3H]thymidine incorporation into avian chondrocytes. In the present study of mammalian systems, we demonstrate differential effects of defined synthetic PTH fragments on CK activity and DNA synthesis, as compared with cyclic AMP production, in osteoblast-enriched embryonic rat calvaria cell cultures, in an osteoblast-like clone of rat osteosarcoma cells (ROS 17/2.8) and in chondroblasts from rat epiphysial cartilage cell cultures. Unlike full-length bovine (b)PTH-(1-84) or the fully effective shorter fragment human (h)PTH-(1-34), fragments lacking the N-terminal region of the hormone did not increase cyclic AMP formation, whereas they did stimulate increases in both DNA synthesis and CK activity. Moreover, the PTH fragment hPTH-(28-48) at 10 /M inhibited the increase in cyclic AMP caused by 10 nm-bPTH-(1-84). The increase of CK activity in ROS 17/2.8 cells caused by bPTH-(1-84) or hPTH-(28-48) was completely inhibited by either cycloheximide or actinomycin D, as was shown previously for rat calvaria cell cultures. These results indicated the presence of a functional domain of PTH in the central part of the molecule which exerts its mitogenic-related effects on osteoblast-and chondroblast-like cells in a cyclic AMP-independent manner. Since cyclic AMP formation by PTH leads to bone resorption, specific mid-region fragments of PTH might prove suitable for use in vivo to induce bone formation without concomitant resorption. INTRODUCTIONIn conjunction with its regulation of calcium homeostasis, parathyroid hormone (PTH) can stimulate both net bone formation and resorption, depending on the conditions of application. Increased levels of cyclic AMP [1] are considered to mediate the action of PTH in causing bone resorption [2] and stimulation of ornithine decarboxylase activity [3,4]. On the other hand, PTH has also been shown to exert proliferative and anabolic effects,

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Section: Introductionsupporting

confidence: 52%

“…2), there was no significant increase in cyclic AMP production at any of the concentrations tested [from 10 nm, the optimum for bPTH-(1-84), to (Figs. 1 and 2) and in the chick sternum chondrocyte system [15].…”

Section: Resultsmentioning

confidence: 99%

Stimulation by defined parathyroid hormone fragments of cell proliferation in skeletal-derived cell cultures

Sömjen¹,

Binderman

Schlüter

et al. 1990

Biochemical Journal

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“…One possible site could be the osteoblast, which possesses high affinity receptors for IL-I [22] and PTH [23]. Their activation leads to elevated prostaglandin synthesis [24] and increased inositolphospholipid turnover [25]. These may be mechanisms which can be affected by immunologically active and inactive cyclosporines as it has already been reported for CsA and calmodulin binding [26,27].…”

Section: Discussionmentioning

confidence: 96%

Different inhibitory actions of cyclosporine A and cyclosporine A-acetate on lipopolysaccharide-, interleukin 1-, 1,25 dihydroxyvitamin D3- and parathyroid hormone-stimulated calcium and lysosomal enzyme release from mouse calvariain vitro

Tullberg-Reinert¹,

Hefti²

1991

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The effects of cyclosporine A (CsA) and one of its immunologically inactive structural analogues, cyclosporine A acetate (CsA-A) on lipopolysaccharide (LPS)-, interleukin-1 (IL-1)-, 1,25 dihydroxyvitamin D3 (1,25 D3)- and parathyroid hormone (PTH)-stimulated bone resorption were tested in mouse calvaria cultures. The release of calcium and a lysosomal enzyme, N-acetylglycosaminidase (NAG) was determined after 3 days of culture. All bone resorbing agents potently stimulated calcium and NAG release. At therapeutic concentration levels of 0.1 and 1.0 micrograms/ml, the immunologically active CsA was significantly more potent than the inactive CsA-A against LPS- and 1,25 D3-induced calcium and NAG release. The inhibition by both cyclosporines of IL-1 and PTH stimulated calcium release was not significantly different. CsA was however more potent than CsA-A against IL-1 stimulated NAG release. PTH-stimulated NAG release was not inhibited by CsA or CsA-A. These findings suggest that both cyclosporines interfere with more than one mechanism of activation of bone resorption. The specific effect of CsA against LPS and 1,25 D3 may be related to its known inhibition of immune cell derived cytokine expression.

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“…IP 3 accumulation [41]. Therefore, it would be interesting to study the effect of EGF on IP 3 formation and protein kinase C activation which could provide an explanation for the less potent effect of EGF on forskolin-stimulated 1,25(OH)2D 3 receptor up-regulation.…”

Section: Discussionmentioning

confidence: 99%

Modulation by epidermal growth factor of the basal 1,25(OH)2D3 receptor level and the heterologous up-regulation of the 1,25(OH)2D3 receptor in clonal osteoblast-like cells

et al. 1991

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Summary. The effects of epidermal growth factor (EGF) on basal 1,25-dihydroxyvitamin D 3 (1,25-(OH)2D3) receptor level and on parathyroid hormone (PTH)-induced 1,25-(OH)2D3 receptor up-regulation were studied in the phenotypically osteoblastic cell line UMR 106. EGF in concentrations exceeding 0.1 ng/ml reduced the number of 1,25(OH)2D 3 binding sites without changing the binding affinity. Maximal reduction was 30% at about 1 ng/ml. This reduction was independent of a change in cAMP content. EGF dose-dependently attenuated both PTH-induced 1,25(OH)2D 3 receptor up-regulation and PTH-stimulated cAMP production, without an effect on the EDso of the PTH effects. For both PTH responses the IC5o and the maximal effective dose were similar, 0.1 ng/ml and 1 ng/ml EGF, respectively. Reduction was first seen at 0.01 ng/ml EGF. At this concentration, EGF reduced PTH-stimulated 1,25-(OH)2D 3 receptor binding without an inhibition of the cAMP response. Time-course studies with 1 ng/ml EGF revealed that at 2 h preincubation EGF reduced the heterologous upregulation by PTH, and maximal inhibition was seen after 4 h. In contrast, PTH-stimulated cAMP production was just significantly inhibited only after 6 h, with 60% inhibition after 24 h preincubation. The effects of prostaglandin E 2 and forskolin on both 1,25(OH)eD3 binding and cAMP production were inhibited in a similar fashion. On the other hand, dibutyryl cAMP-and 3-isobutyl-l-methylxanthinestimulated 1,25(OH)2D3 binding were not affected by EGF. Taken together, our results demonstrate that EGF reduces both the basal number of 1,25(OH)2D3 binding sites and the heterologous up-regulation of the 1,25(OH)2D 3 receptor. The current data suggest that EGF reduces heterologous upregulation of the 1,25(OH)2D3 receptor independent of as well as dependent on the cAMP messenger system. The EGF effect is not primarily located at the PTH receptor, at cAMP phosphodiesterase, or at protein kinase A level.Key words: EGF-1,25(OH)zD 3 binding -PTH -Osteoblast cell line.1,25-Dihydroxyvitamin D 3 (1,25(OH)2D3) and parathyroid hormone (PTH) play an important role in calcium homeostasis. One of the target tissues for 1,25(OH)2D3 and PTH is bone. For both hormones the receptors in bone are located on the osteoblast [1][2][3][4]. From in vitro as well as in vivo studies, evidence has been obtained indicating that 1,25 (OH)2D 3 and PTH act in an interrelated fashion [5,6]. Also at the level of the osteoblast, interactions between 1,25(OH)2D 3 and PTH have been reported. For instance, preincubation of osteoblast-like cells with 1,25(OH)2D 3 attenuates the stimulation of cAMP production by PTH [7][8][9][10]. Furthermore, we have recently reported that PTH and PTHrelated protein cause heterologous up-regulation of the 1,25(OH)2D3 receptor [11].It has been shown that besides these two well-known calciotrophic hormones, growth factors and cytokines also affect bone cell metabolism. One of these polypeptide growth factors is epidermal growth factor (EGF) which has been shown to stimulate bone resorpti...

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Parathyroid hormone and prostaglandin E2 stimulate both inositol phosphates and cyclic AMP accumulation in mouse osteoblast cultures

Cited by 97 publications

References 33 publications

Stimulation by defined parathyroid hormone fragments of cell proliferation in skeletal-derived cell cultures

Stimulation by defined parathyroid hormone fragments of cell proliferation in skeletal-derived cell cultures

Different inhibitory actions of cyclosporine A and cyclosporine A-acetate on lipopolysaccharide-, interleukin 1-, 1,25 dihydroxyvitamin D3- and parathyroid hormone-stimulated calcium and lysosomal enzyme release from mouse calvariain vitro

Modulation by epidermal growth factor of the basal 1,25(OH)2D3 receptor level and the heterologous up-regulation of the 1,25(OH)2D3 receptor in clonal osteoblast-like cells

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