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

Abstract

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 ...

Effect of Intermittent PTH(1–34) on Human Periodontal Ligament Cells Transplanted into Immunocompromised Mice

“…The authors concluded from their work that intermittent PTH(1-34) for 3 weeks is sufficient to enhance bone formation without enhancing resorption. 41 In accordance with these considerations, our results indicate a significant anabolic effect of PTH , as evidenced by the enhanced expression of markers of osteoblastic differentiation and biomineralization and also by serum osteocalcin levels in the PTH(1-34)-treated mice.…”

“…Among others, osteocalcin was demonstrated to be influenced by PTH treatment under different conditions and in different mouse gene types. 41 The mentioned study demonstrated that serum osteocalcin levels were significantly increased after PTH exposure. The authors concluded from their work that intermittent PTH(1-34) for 3 weeks is sufficient to enhance bone formation without enhancing resorption.…”

“…According to Sheehan et al, 41 the anabolic effect of intermittent PTH on bone varies with the species studied as well as with the duration and mode of its administration. One measure to verify a systemic response to subcutaneously injected PTH is the quantification of serum markers of bone turnover.…”

Influence of Mechanical Force on Bone Matrix Proteins in Ovariectomised Mice and Osteoblast-like MC3T3-E1 Cells

“…Sections were then incubated at 37˚C for 15-20 min in freshly prepared acetate-tartaric acid buffer (pH 5.0) containing 0.5 mg/ml naphthol ASMX phosphate and 1.1 mg/ml Fast Red TR (TRAP substrate). After washing with distilled water, tissues were counterstained with aqueous haematoxylin and mounted with Vectamount (Vector Laboratories, Inc., Burlingame, CA, USA) (23).…”

“…The number of cells was determined in five tissue sections spanning 100 μm of tissue. Data are expressed as the mean number of cells per 1.0 mm of perimeter trabecular bone (23).…”