Human Parathyroid Hormone Carboxyterminal Peptide (53-84) Stimulates Alkaline Phosphatase Activity in Dexamethasone-Treated Rat Osteosarcoma Cells in Vitro

Murray, Timothy M.; Rao, L.G.; Muzaffar, S. A.; Ly, Hao

doi:10.1210/endo-124-2-1097

Cited by 75 publications

(40 citation statements)

References 8 publications

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“…Effect of PTH Analogs on Proteoglycan Synthesis-To determine the specificity of the response, we compared the effects of PTH-(1-34) and PTH-(53-84), a fragment that does not stimulate cAMP accumulation but does stimulate alkaline phosphatase and osteocalcin production in osteoblasts (18,19). In addition, PTHrP-(1-34), which is similar to PTH-(1-34) in a variety of biological activities, was also evaluated.…”

Section: Effect Of Rat Pth-(1-34) Treatment Time On Proteoglycanmentioning

confidence: 99%

Parathyroid Hormone-(1–34) Enhances Aggrecan Synthesis via an Insulin-like Growth Factor-I Pathway

Frolik

Chandrasekhar

1999

Journal of Biological Chemistry

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During endochondral bone formation, the growth plate chondrocytes proliferate, become hypertrophic, lose the cartilage phenotype, undergo mineralization, and provide a scaffold upon which subsequent longitudinal bone growth occurs. Parathyroid hormone (PTH), a calcium-regulating hormone, and parathyroid hormone-related peptide (PTHrP), which shares several properties with PTH, have profound effects on skeletal growth and new bone formation. In order to define further the mechanism by which PTH/PTHrP promotes the cartilage phenotype, chondrocytes isolated from the rib cages of developing rat embryos were evaluated for the biosynthesis of aggrecan. Cells treated with PTH-(1-34) for a 4-h period followed by a 20-h recovery period showed a significant increase in cartilage proteoglycan (aggrecan) synthesis in a dose-dependent manner. Only N-terminally intact PTH and PTHrP were effective in stimulating aggrecan synthesis. Addition of a neutralizing antibody to insulin-like growth factor-I (IGF-I) during PTH treatment resulted in the inhibition of PTHstimulated aggrecan synthesis, whereas the addition of a neutralizing antibody to insulin-like growth factorbinding protein-2 (IGFBP-2) resulted in an increase in synthesis in both the control and PTH-treated cells. In addition, PTH treatment resulted in an increase in the mRNA for aggrecan, a reduction in IGFBP-3 mRNA, and no discernible changes in IGF-I mRNA levels, which was complemented by quantitative changes in IGFBP-3 and free IGF-I levels. The reciprocal relationship in the expression of aggrecan and IGFBP was further confirmed in chondrocytes from various gestational stages during normal development. Collectively, our results indicate that the effect of PTH may be mediated at least in part through the regulation of the IGF/IGFBP axis, by a decrease in the level of IGFBP-3, and an increase in free IGF-I levels. It is likely that the local increase in IGF-I may lead to an increase in cartilage type proteoglycan synthesis and maintenance of the cartilage phenotype.

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Section: Effect Of Rat Pth-(1-34) Treatment Time On Proteoglycanmentioning

confidence: 99%

Parathyroid Hormone-(1–34) Enhances Aggrecan Synthesis via an Insulin-like Growth Factor-I Pathway

Frolik

Chandrasekhar

1999

Journal of Biological Chemistry

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“…However, other putative receptors for both ligands have been found (12)(13)(14)(15)(16)(17), and one has been cloned (18). That the PTH/PTHrP receptor mediates the calcium-regulating action of PTH has been demonstrated by the inability of PTH to stimulate 45 Ca release from calvariae of PTH/PTHrP receptor-deficient (PTH/PTHrP-R -/-) mice (19).…”

Section: Introductionmentioning

confidence: 99%

“…The delay in cell differentiation specific to the PTH/PTHrP-R -/-bones could be explained by (a) the inability of PTH to compensate for the lack of PTHrP action on the PTH/PTHrP receptor; (b) effects of the increased levels of PTH observed in these animals (C. Kovacs et al, unpublished observations) on a distinct PTH-specific receptor; or (c) effects of PTHrP independent of the PTH/PTHrP receptor. Additional receptors for PTH (14,16,18) and PTHrP (13,29,30) have been described or postulated to explain actions of the ligands. In addition, PTHrP may have direct nuclear actions (31).…”

mentioning

confidence: 99%

Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development

Lanske

Amling²,

Neff³

et al. 1999

J. Clin. Invest.

223

129

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The formation of the skeleton depends on the differentiation, function, and interaction of various cell types. Two distinct developmental patterns occur. Most bones are formed by endochondral ossification, in which a cartilage mold is replaced by bone. First, mesenchymal cells condense and differentiate into chondrocytes. The chondrocytes in the center of the shaft become hypertrophic and synthesize a distinct extracellular matrix that rapidly becomes mineralized. Osteoclasts then resorb this matrix, allowing blood vessel invasion, and osteoblasts bind to the cartilaginous matrix remnants and deposit bone matrix around them. Later, the remnants are removed and replaced by bone matrix. At the ends of the bone, the epiphyseal growth plates are formed when chondrocytes nearest the ends of bones proliferate and then undergo hypertrophy. A second process by which bone is formed is intramembranous ossification, in which matrix is deposited directly in the mesenchyme by osteoblasts, without replacement of a cartilage matrix. In the long bones, bone collar osteoblasts first participate in intramembranous ossification in the mesenchyme adjacent to the most hypertrophic chondrocytes.Many signaling systems control bone formation. The PTH/PTHrP receptor is at the center of one such system. This receptor integrates signals from both the calciumregulating hormone parathyroid hormone (PTH) and the paracrine factor parathyroid hormone-related protein (PTHrP). PTH is known to influence bone formation in various ways (1). In cultured cells, PTH decreases the production of type I collagen (2) and can enhance the synthesis of noncollagenous proteins, including osteocalcin (3, 4) and interstitial collagenase (collagenase 3; ref. 5). PTH can decrease both the proliferation of osteoblasts (6) and the formation of bone nodules from osteoprogenitor cells in vitro (7). On the other hand, in vivo PTH can increase bone formation, particularly when administered intermittently, and in trabecular bone (8). While the effects of PTHrP on osteoblasts are poorly characterized, the effects of PTHrP on growth plate chondrocytes have been demonstrated by the phenotype of the PTHrP -/-mouse (9). This phenotype shows that PTHrP slows the differentiation of chondrocytes in the growth plate (10).The PTH/PTHrP receptor is found in cells of the kidney tubule and in chondrocytes and osteoblasts of bone (11), and thus might mediate many actions of both PTH and PTHrP. However, other putative receptors for both ligands have been found (12-17), and one has been cloned (18). That the PTH/PTHrP receptor mediates the calcium-regulating action of PTH has been demonstrated by the inability of PTH to stimulate 45 Ca release from calvariae Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) bind to and activate the same PTH/PTHrP receptor. Deletion of either the PTHrP gene or the PTH/PTHrP receptor gene leads to acceleration of differentiation of growth plate chondrocytes. To explore further the functional relationships of PTHrP and the PTH/PTH...

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“…A C-terminal peptide of human PTH (i.e. PTH-(53-84)) elicits a number of biological responses in rat osteosarcoma cells (21,22) yet fails to bind to the human PTH/PTHRP receptor type I stably expressed in human embryonic kidney (HEK-293) cells (23). Thus, it is possible that the biological activity of some of these N-and C-terminal analogues is actually elicited by selective binding to other, as yet uncharacterized, PTH/PTHRP receptors.…”

mentioning

confidence: 99%

Structurally Diverse N-terminal Peptides of Parathyroid Hormone (PTH) and PTH-related Peptide (PTHRP) Inhibit the Na+/H+ Exchanger NHE3 Isoform by Binding to the PTH/PTHRP Receptor Type I and Activating Distinct Signaling Pathways

Azarani

Goltzman

Orlowski

1996

Journal of Biological Chemistry

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Human Parathyroid Hormone Carboxyterminal Peptide (53-84) Stimulates Alkaline Phosphatase Activity in Dexamethasone-Treated Rat Osteosarcoma Cells in Vitro

Cited by 75 publications

References 8 publications

Parathyroid Hormone-(1–34) Enhances Aggrecan Synthesis via an Insulin-like Growth Factor-I Pathway

Parathyroid Hormone-(1–34) Enhances Aggrecan Synthesis via an Insulin-like Growth Factor-I Pathway

Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development

Structurally Diverse N-terminal Peptides of Parathyroid Hormone (PTH) and PTH-related Peptide (PTHRP) Inhibit the Na+/H+ Exchanger NHE3 Isoform by Binding to the PTH/PTHRP Receptor Type I and Activating Distinct Signaling Pathways

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