Human Parathyroid Hormone 1–34 Reverses Bone Loss in Ovariectomized Mice

Alexander, Joseph M.; Bab, Itai; Fish, Susan S.; Müller, Ralph; Uchiyama, Toru; Gronowicz, Gloria; Nahounou, Marcia; Zhao, Qinpeng; White, David W.; Chorev, Michael; Gazit, Dan; Rosenblatt, Michael

doi:10.1359/jbmr.2001.16.9.1665

Cited by 150 publications

(114 citation statements)

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“…Moreover, an adequate number of trabeculae must also be present at the onset of PTH administration for maximal effect [17,40]. PTH has been shown to augment cancellous bone mass when cancellous bone volumes (determined by histomorphometry) are greater than ~9% but not lower than 6% [10,11,40,41]. Since cancellous bone volumes in rodents have historically been determined with histomorphometry, it's difficult to compare our observations with those reported above, a limitation of our approach.…”

Section: Discussionmentioning

confidence: 90%

“…Since cancellous bone volumes in rodents have historically been determined with histomorphometry, it's difficult to compare our observations with those reported above, a limitation of our approach. Indeed, while treatment effects trend in the same direction, there is great disparity between the percent of cancellous bone volume identified by µCT compared to histomorphometery [41]. Unfortunately our laboratory is presently unable to perform bone histomorphometric analyses.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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“…A region of interest including only cancellous bone was constructed, beginning 0.25 mm proximal to the growth plate and extending proximally for 1.25 mm. Images were reconstructed, filtered, and thresholded as previously described (24). The images were stored in three-dimensional arrays with an isotropic voxel size of either 34 m (for the whole bone) or 9 m (for the distal femoral metaphysis).…”

Section: Methodsmentioning

confidence: 99%

Osteoblast-specific Knockout of the Insulin-like Growth Factor (IGF) Receptor Gene Reveals an Essential Role of IGF Signaling in Bone Matrix Mineralization

Zhang

Xuan

Bouxsein

et al. 2002

Journal of Biological Chemistry

642

561

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To examine the local actions of IGF signaling in skeletal tissue in a physiological context, we have used Cremediated recombination to disrupt selectively in mouse osteoblasts the gene encoding the type 1 IGF receptor (Igf1r). Mice carrying this bone-specific mutation were of normal size and weight but, in comparison with normal siblings, demonstrated a striking decrease in cancellous bone volume, connectivity, and trabecular number, and an increase in trabecular spacing. These abnormalities correlated with a striking decrease in the rate of mineralization of osteoid that occurred despite an unexpected osteoblast and osteoclast hyperactivity, detected from the significant increments in both osteoblast and erosion surfaces. Our findings indicate that IGF1 is essential for coupling matrix biosynthesis to sustained mineralization. This action is likely to be particularly important during the pubertal growth spurt when rapid bone formation and consolidation are required.Body size and linear bone growth in mammals is affected by cellular signaling pathways controlled by growth factors and hormones (1). In this regard, a major growth-promoting signaling system consisting of the insulin-like growth factors (IGF, 1 IGF1 and IGF2) and the type 1 IGF receptor (IGF1R) regulates embryonic growth, as shown by gene knockout experiments in mice (1). IGF1 acting through IGF1R also plays central roles in postnatal growth either independently or by mediating growth hormone functions (2). Signaling through the IGF1R tyrosine kinase receptor not only promotes cell proliferation, but also mediates anti-apoptotic actions (3, 4). The IGF system includes a second receptor (IGF2R) devoid of signaling properties, but serving IGF2 turnover, and at least six IGF-binding proteins (IGFBPs) of obscure functional significance (single and also some double mouse mutations ablating IGFBPs have not revealed as yet significant consequences in growth impairment). 2 The IGFs are produced locally in various tissues, including bones, and exert autocrine/paracrine functions, but they are also present in serum, mostly associated with IGFBPs. Whether the circulating IGFs act systemically as hormones is currently controversial (5, 6).A number of in vitro and in vivo studies are progressively unraveling the significance of the IGF system for skeletal development and metabolic control (for a review see Ref. 7). IGF1, by stimulating the proliferation of chondrocytes in the growth plate, plays an essential role in longitudinal bone growth (2) and is also involved in the formation of trabecular bone. In fact, chondrocytes and bone cells produce IGFs and express IGF1R (see for example Refs. 8 and 9). Studies using osteoblast culture systems have shown that IGF1 stimulates osteoblast proliferation, accelerates their differentiation, and enhances bone matrix production (10, 11). In addition, IGF1 is being recognized as a critical factor for bone cell survival (12)(13)(14). Finally, IGF1 also appears to regulate bone resorption, either directly or through its actio...

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“…Images were reconstructed, filtered and thresholded as described previously, with the threshold determined after pilot scans on several specimens. 22 …”

Section: Radiographic Evaluationmentioning

confidence: 99%

Delayed administration of adenoviral BMP-2 vector improves the formation of bone in osseous defects

et al. 2007

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The direct, local, administration of adenovirus carrying human BMP-2 cDNA (Ad.BMP-2) heals critical-sized femoral bone defects in rabbit and rat models. However, the outcome is suboptimal and the technology needs to provide a more reliable and uniform outcome. To this end, we investigated whether the timing of Ad.BMP-2 administration influenced the formation of mineralized tissue within the defect. Criticalsized defects were created in the femora of 28 SpragueDawley rats. Animals were injected intralesionally with a single, percutaneous injection of Ad.BMP-2 (4 Â 10 8 plaqueforming units) either intraoperatively (day 0) or 24 h (day 1), 5 days or 10 days after surgery. The femora were evaluated 8 weeks after surgery by X-ray, microcomputed tomography, dual-energy X-ray absorptiometry and biomechanical testing. The incidence of radiological union was markedly increased when administration of Ad.BMP-2 was delayed until days 5 and 10, at which point 86% of the defects healed. These time points also provided greater bone mineral content within the defect site and improved the average mechanical strength of the healed bone. Thus, delaying the injection of Ad.BMP-2 until 5 or 10 days after surgery enables a greater percentage of critical-sized, segmental defects to achieve radiological union, producing a repair tissue with enhanced mineralization and greater mechanical strength.

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Human Parathyroid Hormone 1–34 Reverses Bone Loss in Ovariectomized Mice

Cited by 150 publications

References 57 publications

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

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

Osteoblast-specific Knockout of the Insulin-like Growth Factor (IGF) Receptor Gene Reveals an Essential Role of IGF Signaling in Bone Matrix Mineralization

Delayed administration of adenoviral BMP-2 vector improves the formation of bone in osseous defects

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