PTH elevates inositol polyphosphates and diacylglycerol in a rat osteoblast-like cell line

Civitelli, Roberto; Reid, Ian R.; Westbrook, S.; Avioli, Louis V.; Hruska, Keith A.

doi:10.1152/ajpendo.1988.255.5.e660

Cited by 101 publications

(71 citation statements)

References 30 publications

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“…There is a general consensus that the hormone stimulates cAMP formation, but in addition, several laboratories reported activation of P! turnover, PKC or calcium mobilization [1,[19][20][21][22][23]. The latter signal has been proposed to arise independently of the formation of IP 3 [24], and studies carried out in our hands are in agreement with this notion (K. Seuwen and H. Boddeke, manuscript in preparation).…”

Section: Discussionsupporting

confidence: 80%

A C‐terminally truncated human parathyroid hormone receptor is functional and activates multiple G proteins

1994

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We have investigated the role of the C-terminal cytoplasmic domain of the human PTH receptor in effector coupling. Following transient expression in COS-1 cells, coupling to both AC and PI-PLC was observed with the full-length receptor. Progressive C-terminal truncations did not dissociate activation of the two signalling systems. In stably transfected 293 cells, however, the full-length receptor as well as the majority of truncated constructs stimulated AC exclusively but failed to activate PI-PLC. Activation of both signalling systems was again observed following stable expression of a severely truncated receptor (R483) in 293 cells. In this case, pertussis toxin was also found to potentiate the cAMP response to hPTH-(1-38) significantly, indicating functional coupling of R483 to Gi proteins. Our results suggest that a core region of the human PTH receptor (first, second, third intracellular loop) can interact promiscuously with different G proteins and that the C-terminus of the full-length receptor directs the receptor towards an interaction with G~.Key words." Parathyroid hormone; Receptor; G protein; Adenylyl cyclase; Phosphoinositide 1, IntroductionPTH is a major regulator of bone and mineral metabolism. In its target cells, which are primarily osteoblasts and kidney proximal tubule cells, the hormone elicits a multitude of responses which are not readily explained solely on the basis of its capacity to stimulate AC (see [1,2] for review). Receptors for PTH have been cloned from opossum, rat, and human cDNA libraries [3][4][5][6]. These receptors bind PTH, PTH-related peptide, and N-terminal fragments of these hormones with nanomolar affinities. Only one PTH receptor gene exists in the mouse, rat, and human genome [7] and so far, there is no evidence lbr receptor subtypes mediating different physiological effects [5].Importantly, the rat and human receptor activate both cAMP and IP production following transient expression in COS cells [4,6]. Stimulation of both signal transduction systems has also been observed with the structurally related calcitonin receptor [8]. Studies presented in abstract form [9] concerning the full-length and a truncated opossum PTH receptor (OK-H, see Fig. 1) had suggested that regions within the C-terminus of the PTH receptor play an important role in the activation of PI turnover, whereas they are dispensable for the coupling to AC.Given these results, we set out to study the coupling specificity of the full-length human PTH receptor, which we had recently cloned from a kidney cDNA library [6], as well as a number of receptor constructs truncated in the C-terminal intracellular tail region. Coupling to AC and PI-PLC was inves-*Corresponding author. Fax: (41) (61) 324 4774.Abbreviations: AC, adenylyl cyclase; Gs and G~, stimulatory and inhibitory G protein of adenytyl cyclase, respectively; Gq, stimulatory G protein of PI-PLC; IP, inositol phosphate; PI, phosphoinositide; PI-PLC, phosphoinositide-specific phospholipase C; PTH, parathyroid hormone; hPTH, human parathyroi...

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Section: Discussionsupporting

confidence: 80%

A C‐terminally truncated human parathyroid hormone receptor is functional and activates multiple G proteins

1994

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“…In bone, the PTH receptor (PTH1R), a seven-transmembrane domain receptor coupled to G-proteins, is highly expressed in osteoblasts and osteocytes (13). Binding of PTH to its receptor immediately activates two well defined signal transduction pathways in osteoblasts: the PKA pathway (14) in which G␣ s stimulates production of cAMP and activation of PKA, and PKC pathway (15) in which G␣ q activates phospholipase C␤ with subsequent formation of diacylglycerol and 1,4,5-inositol trisphosphate and PKC activation. We and others (16) have demonstrated that PKA pathway is the major route responsible for the anabolic action of PTH on bone in rodents.…”

Section: Pth1-34 or Wnt Agonist As Possible Therapy For Radiation-indmentioning

confidence: 99%

PTH1–34 Blocks Radiation-induced Osteoblast Apoptosis by Enhancing DNA Repair through Canonical Wnt Pathway

Chandra¹,

Lin

Zhu³

et al. 2015

Journal of Biological Chemistry

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Background: PTH1-34 alleviates radiation-induced osteoporosis in a preclinical radiotherapy model. Results: PTH1-34 attenuates radiation damage on osteoblasts by increasing Ku70 amount, accelerating DNA repair, and suppressing osteoblast apoptosis. Pathway analyses identify canonical Wnt pathway as an important mediator. Conclusion: PTH1-34 blocks radiation-induced osteoblast apoptosis through activation of ␤-catenin. Significance: PTH1-34 or Wnt agonist could be possible therapy for radiation-induced osteoporosis.

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“…3A). PTH signals through both PKA and PKC pathways after binding with its receptor, PTH1R, on the osteoblast membrane (22,23). To study which pathway PTH uses to regulate MCP-1, we took advantage of different peptide fragments of PTH that activate different pathways as well as inhibitors and activators of these pathways.…”

Section: Pth Stimulation Of Mcp-1 Is Dose-dependent Via the Pka Pathwmentioning

confidence: 99%

Parathyroid Hormone Stimulates Osteoblastic Expression of MCP-1 to Recruit and Increase the Fusion of Pre/Osteoclasts

Li¹,

Qin²,

Bergenstock³

et al. 2007

Journal of Biological Chemistry

194

161

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The clinical findings that alendronate blunted the anabolic effect of human parathyroid hormone (PTH) on bone formation suggest that active resorption is involved and enhances the anabolic effect. PTH signals via its receptor on the osteoblast membrane, and osteoclasts are impacted indirectly via the products of osteoblasts. Microarray with RNA from rats injected with human PTH or vehicle showed a strong association between the stimulation of monocyte chemoattractant protein-1 (MCP-1) and the anabolic effects of PTH. PTH rapidly and dramatically stimulated MCP-1 mRNA in the femora of rats receiving daily injections of PTH or in primary osteoblastic and UMR 106-01 cells. The stimulation of MCP-1 mRNA was dose-dependent and a primary response to PTH signaling via the cAMP-dependent protein kinase pathway in vitro. Studies with the mouse monocyte cell line RAW 264.7 and mouse bone marrow proved that osteoblastic MCP-1 can potently recruit osteoclast monocyte precursors and facilitate receptor activator of NF-B ligand-induced osteoclastogenesis and, in particular, enhanced fusion. Our model suggests that PTH-induced osteoblastic expression of MCP-1 is involved in recruitment and differentiation at the stage of multinucleation of osteoclast precursors. This information provides a rationale for increased osteoclast activity in the anabolic effects of PTH in addition to receptor activator of NF-B ligand stimulation to initiate greater bone remodeling. Parathyroid hormone (PTH)2 is a principal hormone regulating bone remodeling via its actions on both bone formation and bone resorption. The finding that the anabolic effect of human PTH-(1-34) on bone formation was blunted when bone resorption was inhibited indicated that active resorption is involved and enhances the in vivo anabolic effect of PTH (1-3). However, the molecular basis of the osteoclast activation in this process has not been fully studied. In order to identify the key mediators for the anabolic effects of PTH, we performed microarray using RNA from the femora of 3-month-old Sprague-Dawley female rats injected daily with hPTH-(1-34) to increase bone formation or vehicle. This was compared with rats receiving hPTH-(1-34) in a catabolic protocol by continuous infusion. PTH-(1-34) regulated numerous genes (ϳ1,000), but differentially, in both regimes (see accompanying article, Ref. 4). Notably, in the anabolic protocol, a number of cytokines and chemokines, RANKL, interleukin-6, CXCL1, and CCL2 (MCP-1), were highly induced. In contrast, none of these were significantly increased, by microarray, in the catabolic protocol. The chemokine, monocyte chemoattractant protein-1 (MCP-1, CCL2), was found to be the most highly stimulated gene from 14-day intermittent hPTH-(1-34) or hPTH-(1-31) administration (both cause over 100-fold changes). With continuous infusion of PTH, the MCP-1 mRNA was elevated less than 2-fold, and this difference indicates a potentially important role for MCP-1 in the anabolic effect of PTH.Chemokines are bioactive peptides that regulate leuk...

show abstract

PTH elevates inositol polyphosphates and diacylglycerol in a rat osteoblast-like cell line

Cited by 101 publications

References 30 publications

A C‐terminally truncated human parathyroid hormone receptor is functional and activates multiple G proteins

A C‐terminally truncated human parathyroid hormone receptor is functional and activates multiple G proteins

PTH1–34 Blocks Radiation-induced Osteoblast Apoptosis by Enhancing DNA Repair through Canonical Wnt Pathway

Parathyroid Hormone Stimulates Osteoblastic Expression of MCP-1 to Recruit and Increase the Fusion of Pre/Osteoclasts

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