Actions of Parathyroid Hormone

Hock, Janet M.; Fitzpatrick, Lorraine A.; Bilezikian, John P.

doi:10.1016/b978-012098652-1.50129-3

Cited by 27 publications

(20 citation statements)

References 220 publications

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“…Several mechanisms have been proposed for PTH anabolic actions, including cAMP activation [1], growth factors such as IGF-1 [2], transcriptional mediators in bone such as c-Fos [3] and Runx2 [4], and inhibition of apoptosis [5]. Although it has been suggested that PTH exerts anabolic actions in bone by reducing osteoblast apoptosis in mice, clinically it has been shown that PTH-mediated bone formation is associated with an increase in osteoblast apoptosis [6].…”

Section: Introductionmentioning

confidence: 99%

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

Pettway

Meganck

Koh

et al. 2008

Bone

107

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PTH (1-34) is the only FDA-approved anabolic agent for osteoporosis treatment in the U.S., but its mechanisms are not completely understood. This study investigated PTH effects on osteogenic cells at various stages of differentiation and proliferation using an engineered bone growth model in vivo. Ossicles were generated from bone marrow stromal cells (BMSCs) implanted in immunocompromised mice. Three weeks of PTH (40μg/kg/d) or vehicle treatment initiated 1 day, 1, 2, or 3wks after BMSC implantation resulted in an anabolic response in PTH-treated implants (via histomorphometry and microCT) in all treatment groups. A novel in vivo tracking strategy with luciferase tagged BMSCs and weekly bioluminescent imaging of ossicles revealed increased donor cell proliferation in PTH-treated ossicles. The greatest increase occurred during the first week, and the activity remained elevated in PTH-treated implants over time. Zoledronic acid (ZA) was combined with PTH to delineate interactive mechanisms of these bone active agents. Combining ZA with PTH treatment reduced the PTH-mediated increase in luciferase BMSC activity, serum osteocalcin, and serum tartrate resistant acid phosphotase-5b (TRAP-5b) but ZA did not reduce the PTH-induced increase in total bone. Since zoledronic acid reduced PTH-induced proliferation without reducing bone volume, these data suggests that combining PTH and bisphosphonate therapy warrants further investigation in the treatment of bone disorders.

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Section: Introductionmentioning

confidence: 99%

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

Pettway

Meganck

Koh

et al. 2008

Bone

107

View full text Add to dashboard Cite

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“…Thus PTH may contribute, along with PTHrP, to the growth and differentiation of cartilage, has profound hypotensive effects by relaxing resistance-type vessels, has a relaxant effect on gastrointestinal smooth muscle, and may participate in the regulation of calcium metabolism in the central nervous system (Fitzpatrick et al 1992, Hock et al 2002. Whether any or all of these functions, however, are actually mediated by circulating PTH, or rather by locally produced PTHrP, remains speculative.…”

Section: Introductionmentioning

confidence: 99%

The murine gene encoding parathyroid hormone: genomic organization, nucleotide sequence and transcriptional regulation

Tong²,

Hiou-Tim³

et al. 2002

Journal of Molecular Endocrinology

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The type 1 parathyroid hormone receptor (PTHR1) binds, with equal affinity, two ligands with distinct biological functions: PTH, the major peptide hormone controlling calcium homeostasis, and the paracrine factor, PTH-related peptide (PTHrP), a local regulator of cellular proliferation and differentiation. To clarify the complexity of possible interactions between two distinct ligands, PTH and PTHrP, and their common receptor in the intact organism, and to identify as yet unrecognized roles for PTH in normal physiology, we have cloned and characterized the structural organization, nucleotide sequence and transcriptional regulation of the murine gene encoding PTH. One recombinant clone isolated from a mouse genomic library contained 14 kb of DNA, encompassing the entire Pth gene. The transcriptional unit spans 3·2 kb of genomic DNA and, analogous to the human PTH gene, it is interrupted by two introns. The deduced mRNA encodes the 115-amino acid precursor, preproPTH. Comparison of the murine preproPTH sequence with other mammalian forms of the protein shows it to be highly conserved and to share limited structural similarity to PTHrP at the amino-terminal region, a domain critical for binding and activation of their common receptor. Putative binding motifs for the transcription factors sex-determining region Y gene product, transcriptional repressor CDP, hepatic nuclear factor 3β, GATA-binding factor 1, glucocorticoid receptor, SRY-related high mobility group box protein 5 and cAMP response element binding protein were identified in the 5′ flanking region of the Pth gene. When placed upstream of a reporter gene, these sequences failed to confer transcriptional regulation in response to 1,25(OH) 2 vitamin D 3 , but responded positively to the addition of isoproterenol and forskolin. Mutational analysis identified a cAMP-response element in the Pth promoter.

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“…Intermittent administration of PTH has been reported to stimulate bone formation; in contrast, continuous treatment promotes bone resorption (Hock et al 2002;Rubin et al 2002). The anabolic function of PTH is reported to occur through the activation of survival signaling in osteoblasts by delaying osteoblast osteoporosis, which contributes to an increase in cell numbers (Jilka, 2007).…”

Section: Introductionmentioning

confidence: 99%

Role of Gap Junction, Hemichannels, and Connexin 43 in Mineralizing in Response to Intermittent and Continuous Application of Parathyroid Hormone

Cherian

Xia

Jiang

2008

Cell Communication & Adhesion

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Intermittent administration stimulates bone formation, whereas sustained elevation of parathyroid hormone (PTH) as in hyperparathyroidism stimulates bone resorption. Even though PTH(1-34) is the only anabolic agent clinically approved for the treatment of osteoporosis, the molecular mechanism whereby PTH mediates these opposing effects depending on timing of administration is not well understood. In this study, we sought to determine the involvement of gap junctions and hemichannels, and the protein that forms them, connexin 43 (Cx43), in the effect of PTH(1-34) on osteoblast mineralization. The osteoblast-like cell line MLO-A5 that rapidly mineralizes in culture was used. Intermittent PTH enhances mineralization, whereas continuous PTH inhibits this process. The mineralization was significantly inhibited by 18 β-glycyrrhetinic acid, an inhibitor known to block gap junctions and hemichannels. When the cells were treated with PTH(1-34), gap junctional coupling was increased; however, the degree of stimulation was similar between intermittent and continuous treatment. The permeabilization to dye was not detected under various intermittent or continuous PTH treatments. On the other hand, the overall level of Cx43 protein increased in response to continuous PTH treatment. In contrast, when the cells were subjected to intermittent treatment overall level of Cx43 was unchanged, but there was an increase of connexons associated with an increase in Cx43 expression on the cell surface. Our results suggest that Cx43 overall expression, connexon formation and cell surface expression are differentially regulated by intermittent and continuous PTH(1-34), implying the involvement of Cx43 and Cx43-forming channels in mediating the effects of PTH on bone formation.

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Actions of Parathyroid Hormone

Cited by 27 publications

References 220 publications

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

The murine gene encoding parathyroid hormone: genomic organization, nucleotide sequence and transcriptional regulation

Role of Gap Junction, Hemichannels, and Connexin 43 in Mineralizing in Response to Intermittent and Continuous Application of Parathyroid Hormone

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