Dexamethasone-treated ROS 17/2.8 rat osteosarcoma cells are responsive to human carboxylterminal parathyroid hormone peptide hPTH (53–84): Stimulation of alkaline phosphatase

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

doi:10.1007/bf02565133

Cited by 55 publications

(27 citation statements)

References 11 publications

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“…For example, it was proposed that a distinct alkaline phosphatase activity is stimulated by carboxyl-terminal sequences [26]. Although it is not unreasonable to think that the carboxyl-terminal portion of PTH may possess inherent biologic activity, particularly as this region has been highly conserved throughout evolution, no compelling evidence has been produced that it is important for any of the known actions of PTH, including skeletal anabolism.…”

Section: Modern Historymentioning

confidence: 99%

Present at the beginning: a personal reminiscence on the history of teriparatide

Marcus

2011

Osteoporos Int

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The ability of parathyroid glandular extracts to stimulate bone acquisition in rodents was established in the 1920s, but interest in this action lay dormant for almost 50 years until application of contemporary laboratory methods permitted the large-scale production of an amino-terminal fragment of PTH, (1-34) hPTH (teriparatide), which was capable of carrying out all known actions of the full-length (1-84) PTH molecule. In the 1970s, largely stimulated by the efforts of a British pharmacologist, Dr. John Parsons, the scientific community began to revisit these anabolic actions and showed that single daily injections of teriparatide dramatically increased bone mass in several mammalian species and restored bone in oöphorectomized rats. Shortly thereafter, human studies confirmed a striking increase in trabecular bone mass and showed also that an important part of teriparatide's action is to increase cortical bone. Eli Lilly and Company conducted a formal registration trial in postmenopausal women with osteoporosis. The unexpected occurrence of osteosarcomas in Fisher 344 rats treated long-term with teriparatide provoked an abrupt cessation of that trial, but ambiguity concerning the relevance of this rat finding to human disease, combined with significant anti-fracture efficacy, led to FDA approval of teriparatide for men and postmenopausal women with osteoporosis "at high risk for fracture" in 2002. Subsequently, teriparatide has been approved also for treatment of patients with glucocorticoid-associated osteoporosis, and papers indicating utility of this agent for dental and orthopedic applications have begun to appear.

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Section: Modern Historymentioning

confidence: 99%

Present at the beginning: a personal reminiscence on the history of teriparatide

Marcus

2011

Osteoporos Int

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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%

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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“…Urine was also collected for 15 minutes (-15 to 0 minutes) and the bladder washed with 40 ml of water, which was also collected. An infusion of CaCI, (375 pmol of elementary Caikg in 250 ml of 0.45% sodium chloride) at 4 mliminute or of Na,EDTA (210 pmolikg in 250 ml of 0.45% sodium chloride) at 4 ml/ minute was then started and continued for 1 h. Blood and urine samples were obtained at 15,30,45, and 60 minutes after beginning the infusion. The experiment was then terminated and the animals sacrificed by an injection of 20% KCI.…”

Section: Experimental Protocolmentioning

confidence: 99%

Influence of Ca2+ concentration on the clearance and circulating levels of intact and carboxy-terminal iPTH in pentobarbital-anesthetized dogs

D'Amour

Rousseau

Rocheleau

et al. 1996

Journal of Bone and Mineral Research

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The role of hormone secretion and hormone clearance in the differential control of circulating levels of intact (I-) and carboxy-terminal (C-) immunoreactive parathyroid hormone (iPTH) was evaluated in 18 pentobarbital-anesthetized dogs. Catheters were installed in the aorta, left renal, and hepatic veins for sampling. Hepatic and renal blood flows were calculated from sulfobromophtalein (BSP) and p-aminohippuric acid (PAH) extraction and clearance. I- and C-iPTH were measured during a 1 h of infusion of CaCl2 or Na2EDTA. High-performance liquid chromatography (HPLC) profiles of I- and C-iPTH in and out of the liver and kidney were also obtained. Data on two dogs (one CaCl2 and one Na2EDTA infusion) were pooled for the analysis of one parathyroid function using a four-parameter mathematical model. Results obtained in the basal state and during analysis of the parathyroid function were also compared with those of 24 awakened dogs. Results are means +/- SD. Anesthetized dogs had lower levels of Ca2+ (1.29 +/- 0.03 vs. 1.34 +/- 0.04 mmol/l; p < 0.001) and higher levels of I- (11.5 +/- 5.7 vs. 3.0 +/- 1.9 pmol/l, p < 0.001) and C-iPTH (52 +/- 20.9 vs. 22.8 +/- 10.5 pmol/l; p < 0.001) than awakened dogs. Their stimulated (S) and nonsuppressible (NS) I-iPTH levels were increased 2- and 4-fold, respectively, while similar C-iPTH levels rose only 1.35- and 1.75-fold; this caused their S (4.4 +/- 0.7 vs. 6.8 +/- 1.9; p < 0.001) and NS (24.6 +/- 11.8 vs. 49.8 +/- 27.5; p< 0.05) C-iPTH/I-iPTH ratios to decrease. This was not explained by different renal clearance rates of I- and C-iPTH since both were similar at approximately 10 ml/kg/minute and unaffected by Ca2+ concentration. Clearance of all I- and C-iPTH HPLC molecular forms by the kidney appeared equal. A 50% decrease in the hepatic clearance of I-iPTH to approximately 12 ml/kg/minute in pentobarbital-anesthetized dogs, related to a lower hepatic blood flow, explained the higher levels of S and NS I-iPTH in these animals. I-iPTH hepatic clearance was unaffected by Ca2+ concentration. C-iPTH hepatic clearance was much lower at approximately 5 ml/kg/minute, abolished by hypercalcemia, and reduced by the influence of anesthesia on hepatic blood flow. This also explained the higher S C-iPTH levels in anesthetized animals. I-PTH(1-84) detected by the C-iPTH assay explained only 37.6% of the hepatic C-iPTH clearance in hypocalcemia and 73.3% in hypercalcemia. Overall, our results indicate that total C-iPTH clearance is about 40.2% that of I-iPTH in hypocalcemia and 41.3% in hypercalcemia. This would only explain a 2.4- to 2.5-fold difference in circulating levels of I- and C-iPTH if secretion rates were equal; the larger difference observed in S and NS C-iPTH/I-iPTH ratio values is thus mainly explained by different production rates.

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Dexamethasone-treated ROS 17/2.8 rat osteosarcoma cells are responsive to human carboxylterminal parathyroid hormone peptide hPTH (53–84): Stimulation of alkaline phosphatase

Cited by 55 publications

References 11 publications

Present at the beginning: a personal reminiscence on the history of teriparatide

Present at the beginning: a personal reminiscence on the history of teriparatide

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

Influence of Ca2+ concentration on the clearance and circulating levels of intact and carboxy-terminal iPTH in pentobarbital-anesthetized dogs

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