Direct Involvement of cAMP-Dependent Protein Kinase in the Regulation of Alkaline Phosphatase Activity by Parathyroid Hormone (PTH) and PTH-Related Peptide in Osteoblastic UMR-106 Cells

Kano, Junichi; Sugimoto, Toshitsugu; Fukase, Masaaki; Chihara, Kazuo

doi:10.1006/bbrc.1994.1224

Cited by 25 publications

(13 citation statements)

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“…PTH stimulates multiple intracellular signals including protein kinase A (PKA), protein kinase C and inositol phosphate and calcium. The activation of PKA acts as a main pathway in the regulation of ALP activity in MC3T3-E 1 and other osteoblasts [19][20][21]. The inhibition of PTH-stimulated ALP activity by mIL-4 or mIL-13 in the MC3T3-E1 cells may be associated with the inhibition of cAMP generation.…”

Section: H Thymidine Incorporation Of Mc3t3-e1 Cells and Cell Prolifmentioning

confidence: 99%

Interleukin (IL)-4 and IL-13 Inhibit the Differentiation of Murine Osteoblastic MC3T3-E1 Cells.

et al. 2000

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Abstract.Interleukin-4 (IL-4) inhibits the spontaneous and stimulated bone resorption resulting from the inhibition of osteoclast formation, as well as osteoclastic activity. Since IL-13 shares some biological properties with IL-4, it was recently reported that IL-13 inhibits bone resorption.The present study was designed to determine the effects of murine IL-4 (IL-4) and murine IL-13 (IL-13) on the murine osteoblastic cell line MC3T3-E1.IL-4 and IL-13 stimulated 3H-thymidine incorporation in the MC3T3-E1 cells and its proliferation in dose dependent manners. A spontaneous increase in alkaline phosphatase (ALP) activity in the cells after plating was inhibited by IL-4 or IL-13, and both cytokines blunted an increase in ALP activity by human parathyroid hormone (PTH) (1-34).PTHstimulated cyclic AMP (cAMP) production was inhibited by pretreatment with IL-4 and IL-13 for 48 hr in dose dependent manners.Pretreatment with IL-4 and IL-13 for 48 hr caused a decrease in PTH-induced cAMP production at any stimulatory concentration. However, the effective dose (ED50) was unchanged by the pretreatment with these cytokines. Pretreatment with IL-4 and IL-13 did not modulate cAMP generation by forskolin. In contrast, cAMP generation by PGE2 is greater in the cells treated with the cytokines compared to those without the cytokines.These results indicate that IL-4 and IL-13 act on MC3T3-E1 cells in the same manner, stimulating cell proliferation, but inhibiting cell differentiation. The inhibition of osteoblast differentiation by IL-4 and IL-13 may be associated with a decrease in PTH actions on osteoblasts. . Our histomorphometrical study indicated that IL-4 inhibits not only bone resorption but also bone formation in normal and ovariectomized mice in vivo, resulting in a low rate of bone turnover [6] . These in vivo studies [5, 6] suggest that IL-4 also acts on osteoblasts, leading to inhibition of bone formation.IL-13, a recently identified Th2 cytokine, shares some, but not all, of the in vitro functions of IL-4. Each cytokine inhibits the activation of monocytes and macrophages and stimulates human B cells. IL-13 does not act on T cells, whereas IL-4 does. Murine IL-13 (mIL-13) does not act on murine B cells, in contrast to mIL-4 which acts on murine B

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Section: H Thymidine Incorporation Of Mc3t3-e1 Cells and Cell Prolifmentioning

confidence: 99%

Interleukin (IL)-4 and IL-13 Inhibit the Differentiation of Murine Osteoblastic MC3T3-E1 Cells.

et al. 2000

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“…We have used two mem brane-permeable analogs of cAMP: Sp-cAMPS and RpcAMPS in order to investigate whether cAMP can modu late angiogenesis. These compounds are more permeable than 8-bromo-cAMP and have much higher specific affin ity for PKA [18], Sp-cAMPS mimicks the effects of natu ral cAMP by dissociating the catalytic subunit, thereby activating the cAMP-dependent protein kinase, whereas Rp-cAMPS binds to the regulatory subunit of the cAMPdependent protein kinase but does not dissociate the cata lytic subunit [40], Thus Rp-cAMPS is a competitive inhibitor for activators of cAMP-mediated signal trans duction [40], These two cAMP analogs have been used extensively in many cell types, including HUVECs, as tools in order to investigate the involvement of the cAMPsignalling pathway in the regulation of cellular functions [11,17,27,[40][41][42], Using these cAMP analogs and forskolin we have dem onstrated in two angiogenesis model systems that the ele vated intracellular levels of cAMP suppress angiogenesis. In the CAM system in ovo, forskolin and Sp-cAMPS caused a dose-dependent suppression of angiogenesis ( fig.…”

Section: Discussionmentioning

confidence: 99%

Opposing Effects on Modulation of Angiogenesis by Protein Kinase C and cAMP-Mediated Pathways

Tsopanoglou

Haralabopoulos²,

Maragoudakis³

1994

J Vasc Res

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The role of cAMP-mediated pathway in modulating angiogenesis was investigated. We have shown previously that activators of protein kinase C (PKC) caused a marked increase in angiogenesis, while the specific inhibitor of PKC, Ro 318220 suppressed angiogenesis. Here we show that forskolin, which activates adenylate cyclase and elevates the intracellular levels of cAMP, and the Sp-diastereomer of adenosine cyclic-3’,5’-monophosphothioate (Sp-cAMPS), caused a dose-dependent suppression of collagenous protein biosynthesis and angiogenesis in the chick chorioallantoic membrane system (CAM). The opposite modulation of angiogenesis by activators of PKC and elevated cAMP levels was further confirmed by the suppression of 4β-phorbol-12-myristate-13-acetate (4β-PMA)-stimulated angiogenesis by either forskolin or Sp-cAMPS. On the contrary, the Rp-diastereomer of adenosine cyclic-3’,5’-monophospho-thioate (Rp-cAMPS), which antagonises endogenous cAMP biochemical actions, had no effect on angiogenesis alone and did not suppress 4β-PMA stimulated angiogenesis. However, Rp-cAMPS antagonised the effect of forskolin and Sp-cAMPS on 4β-PMA induced angiogenesis. Similar results were obtained in the human umbilical vein endothelial cell tube formation assay. In this system, the PKC inhibitor, Ro 318220, caused a dose-dependent inhibition and 4β-PMA reversed this effect. Also, forskolin and Sp-cAMPS caused an inhibition in tube formation. These results indicate that increased levels of intracellular cAMP have a negative effect in normal angiogenesis and cause a large reduction of the promotion of angiogenesis resulting from PKC activation.

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“…Our previous study revealed that the activation of cAMP-dependent protein kinase was linked to the regulation of TdR and ALP activity in UMR-106 cells [20,21]. In addition, I-PTH is less effective than N-PTH in increasing cAMP production and the intracellular calcium ([Ca2+]i) concentration in these cells [5], so that it is reasonable to ascribe the difference between N-PTH and I-PTH in regulating TdR and ALP activity to the amounts of cAMP produced.…”

Section: Discussionmentioning

confidence: 99%

Carboxyl-Terminal Parathyroid Hormone Fragments Stimulate Type-1 Procollagen and Insulin-Like Growth Factor-Binding Protein-5 mRNA Expression in Osteoblastic UMR-106 Cells.

et al. 1998

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Direct Involvement of cAMP-Dependent Protein Kinase in the Regulation of Alkaline Phosphatase Activity by Parathyroid Hormone (PTH) and PTH-Related Peptide in Osteoblastic UMR-106 Cells

Cited by 25 publications

References 0 publications

Interleukin (IL)-4 and IL-13 Inhibit the Differentiation of Murine Osteoblastic MC3T3-E1 Cells.

Interleukin (IL)-4 and IL-13 Inhibit the Differentiation of Murine Osteoblastic MC3T3-E1 Cells.

Opposing Effects on Modulation of Angiogenesis by Protein Kinase C and cAMP-Mediated Pathways

Carboxyl-Terminal Parathyroid Hormone Fragments Stimulate Type-1 Procollagen and Insulin-Like Growth Factor-Binding Protein-5 mRNA Expression in Osteoblastic UMR-106 Cells.

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