Modulation of osteogenic cell ultrastructure by RS-23581, an analog of human parathyroid hormone (PTH)-related peptide-(1-34), and bovine PTH-(1-34).

Leaffer, David; Sweeney, Michael; Kellerman, Lois; Avnur, Zafrira; Krstenansky, John L.; Vickery, B. H.; Caulfield, John P.

doi:10.1210/endo.136.8.7628402

Cited by 86 publications

(33 citation statements)

References 18 publications

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“…Leaffer et al reported that the increase in osteoblasts covering the surface of cancellous bone of rats following intermittent PTH administration was accompanied by a reciprocal reduction in the number of the flat lining cells that cover the surface of quiescent bone [77]. Following cessation of hormone administration, osteoblast number declined while lining cells increased.…”

Section: Effect Of Intermittent Pth On Lining Cell Activationmentioning

confidence: 99%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

625

531

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Intermittent administration of parathyroid hormone (PTH) stimulates bone formation by increasing osteoblast number, but the molecular and cellular mechanisms underlying this effect are not completely understood. In vitro and in vivo studies have shown that PTH directly activates survival signaling in osteoblasts; and that delay of osteoblast apoptosis is a major contributor to the increased osteoblast number, at least in mice. This effect requires Runx2-dependent expression of antiapoptotic genes like Bcl-2. PTH also causes exit of replicating progenitors from the cell cycle by decreasing expression of cyclin D and increasing expression of several cyclin-dependent kinase inhibitors. Exit from the cell cycle may set the stage for pro-differentiating and pro-survival effects of locally produced growth factors and cytokines, the level and/or activity of which are known to be influenced by PTH. Observations from genetically modified mice suggest that the anabolic effect of intermittent PTH requires insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF-2), and perhaps Wnts. Attenuation of the negative effects of PPARγ may also lead to increased osteoblast number. Daily injections of PTH may add to the pro-differentiating and pro-survival effects of locally produced PTH related protein (PTHrP). As a result, osteoblast number increases beyond that needed to replace the bone removed by osteoclasts during bone remodeling. The pleiotropic effects of intermittent PTH, each of which alone may increase osteoblast number, may explain why this therapy reverses bone loss in most osteoporotic individuals regardless of the underlying pathophysiology.

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Section: Effect Of Intermittent Pth On Lining Cell Activationmentioning

confidence: 99%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

625

531

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“…Thus, these reports suggest that bone anabolism induced by short term intermittent PTH administration is not dependent upon increasing the number of osteoblast progenitors. While de-differentiation of bone lining cells back to osteoblasts may also contribute to increasing osteoblast number [44], they alone are unlikely to be responsible for the total increase in osteoblasts and osteocytes reported following intermittent PTH injections [10].…”

Section: Acknowledgementsmentioning

confidence: 99%

Short-term intermittent PTH 1-34 administration enhances bone formation in SCID/Beige mice

et al. 2010

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Parathyroid hormone (Pth) is an 84 amino acid polypeptide secreted by parathyroid glands in response to low serum calcium. The exogenous administration of PTH can induce both anabolic and catabolic actions in bone; however, such consequences depend upon how PTH is administered. Continuous PTH infusion, similar to the condition of hyperparathyroidism, initiates bone catabolism by enhancing resorption and decreasing formation. In contrast, when administered intermittently (by daily injection), PTH promotes bone formation, as measured by increased bone mass and enhanced mechanical properties [1][2][3][4][5] abstract. The anabolic effect of intermittent PTH on bone is variable depending on the species studied, duration/mode of administration, and location of skeletal response investigated. We tested the hypothesis that low dose, short term, intermittent PTH 1-34 administration is sufficient to enhance bone formation without altering bone resorption. To test our hypothesis, mice were treated intermittently with one of three concentrations of PTH 1-34 (1 μg/kg, low; 10 μg/kg or 20 μg/kg, high) for three weeks. The skeletal response was identified by quantifying: serum markers of bone turnover, cancellous bone parameters in distal femur, proximal tibia, and lumbar vertebrae by µCT, and number of osteoblasts and osteoclasts in distal femur. Mice receiving 20 μg/kg of PTH 1-34 demonstrated a 30% increase in serum osteocalcin, but no differences in serum calcium, type I collagen teleopeptides, or TRACP 5b. For all bones, µCT analysis suggested mice receiving 20 μg/kg of PTH 1-34 had increased cancellous bone mineral density, trabecular thickness and spacing, but decreased trabecular number. A 60% increase in the number of alkaline phosphatase positive osteoblasts in the distal femur was also observed in tissue sections; however, the number of TRAP positive osteoclasts was not different between test and control groups. While animals administered 10 μg/kg demonstrated similar trends for all bone turnover indices, such alterations were not observed in animals administered PTH 1-34 at 1 μg/kg per day. Thus, PTH 1-34, administered intermittently for three weeks at 20 μg/kg is sufficient to enhance bone formation without enhancing resorption.Key words: Parathyroid hormone, Bone turnover, SCID/Beige mouse, Microcomputed tomography full length peptide, the first 34 amino acids (1-34) are sufficient for its biological activity in bone [3,[6][7][8].Daily PTH 1-34 administration, similar to the full length peptide, is thought to increase bone formation primarily by enhancing the number of bone forming osteoblasts [9]. The anabolic action of intermittent PTH 1-34 on the skeleton has been studied widely in rodent models [10][11][12][13][14][15][16][17]. Studies employing murine models suggest the skeletal response to exogenous PTH 1-34 varies depending on the dose and duration of administration, as well as the mouse strain, age, and skeletal site investigated. Investigations of PTH 1-34 action on bone have employed doses ranging from ...

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“…Nonetheless, daily PTH injections stimulated bone formation in rodents without affecting preosteoblast replication (46) or increasing the number of early mesenchymal progenitors (6), and the anabolic effect of the hormone was not hindered in a mouse strain with reduced osteoblastogenesis (6). Intermittent PTH may also increase osteoblast number by transformation of quiescent lining cells into osteoblasts (46,47). This mechanism may be important in periosteal bone (48), where the rate of bone formation is very low compared with that in cancellous bone, reducing the potential contribution of reduced osteoblast apoptosis to the anabolic effect (49).…”

Section: Attenuation Of Osteoblast Apoptosis Plays a Major Role In Thementioning

confidence: 99%

Proteasomal Degradation of Runx2 Shortens Parathyroid Hormone-induced Anti-apoptotic Signaling in Osteoblasts

Bellido

Ali

Plotkin

et al. 2003

Journal of Biological Chemistry

353

297

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It is unknown why sustained elevation of parathyroid hormone (PTH) stimulates bone resorption, whereas intermittent administration stimulates bone formation. We show in mice that daily injections of PTH attenuate osteoblast apoptosis, thereby increasing osteoblast number, bone formation rate, and bone mass, but do not affect osteoclast number. In contrast, sustained elevation of PTH, achieved either by infusion or by raising endogenous hormone secretion with a calcium-deficient diet, does not affect osteoblast apoptosis but increases osteoclast number. Attenuation of apoptosis by PTH in cultured osteoblastic cells requires protein kinase A-mediated phosphorylation and inactivation of the pro-apoptotic protein Bad as well as transcription of survival genes, like Bcl-2, mediated by CREB (cAMP response element-binding protein) and Runx2. But, PTH also increases proteasomal proteolysis of Runx2. Moreover, the anti-apoptotic effect of PTH is prolonged by inhibition of proteasomal activity, by overexpressing a dominant negative form of the E3 ligase (ubiquitin-protein isopeptide ligase) that targets Runx2 for degradation (Smurf1), or by overexpressing Runx2 itself. The duration of the anti-apoptotic effect of PTH, thus, depends on the level of Runx2, which in turn is decreased by PTH via Smurf1-mediated proteasomal proteolysis. The selflimiting nature of PTH-induced survival signaling might explain why intermittent administration of the hormone is required for bone anabolism.Cyclic activation of cell surface receptors often leads to a different biologic response than sustained activation. A classic example is the stimulation of luteinizing hormone and follicle stimulating hormone production by pituitary gonadotroph cells in response to pulsatile gonadotropin releasing hormone (GnRH) versus the inhibition of hormone production by continuous GnRH treatment (1). The differential response of the skeleton to intermittent versus continuous elevation of parathyroid hormone (PTH) 1 is another long known example with important clinical and therapeutic implications. Indeed, chronic elevation of the hormone as in primary or secondary hyperparathyroidism stimulates bone resorption leading to bone loss (2, 3). In contrast, intermittent administration of PTH stimulates new bone formation by increasing osteoblast number (4). Heretofore, a mechanistic explanation for the dependence of this effect on repeated transient increases in PTH has remained unknown. Albeit, intermittent PTH administration by daily injections was recently approved by the United States Food and Drug Administration as the first form of osteoporosis therapy that increases bone mass de novo, reverses the bone deficit, and dramatically reduces the incidence of fractures (5).We had previously shown that daily injections of PTH to mice for 28 days reduces the prevalence of osteoblast apoptosis and increases the number of osteoblasts (6), providing an explanation for the increase in bone formation rate and bone mineral density (BMD) seen with intermittent PTH adminis...

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Modulation of osteogenic cell ultrastructure by RS-23581, an analog of human parathyroid hormone (PTH)-related peptide-(1-34), and bovine PTH-(1-34).

Cited by 86 publications

References 18 publications

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Short-term intermittent PTH 1-34 administration enhances bone formation in SCID/Beige mice

Proteasomal Degradation of Runx2 Shortens Parathyroid Hormone-induced Anti-apoptotic Signaling in Osteoblasts

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