Canine renal receptors for parathyroid hormone. Down-regulation in vivo by exogenous parathyroid hormone.

Mahoney, Cheryl; Nissenson, Robert A.

doi:10.1172/jci110989

Cited by 48 publications

(12 citation statements)

References 31 publications

(31 reference statements)

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“…Consequently, the total number of receptor molecules on the cell surface is reduced, and target cells are protected from overstimulation by excess ligands (down-regulation). The PTH/PTHrP receptor also has been shown to undergo endocytosis after PTH binding (33,34). Both positive and negative regulatory elements controlling endocytosis have been identified in the carboxyl-terminal tail of this receptor (35).…”

Section: Resultsmentioning

confidence: 99%

Megalin Antagonizes Activation of the Parathyroid Hormone Receptor

Hilpert¹,

Nykjaer²,

Jacobsen³

et al. 1999

Journal of Biological Chemistry

110

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Parathyroid hormone (PTH) is predominantly cleared from the circulation by glomerular filtration and degradation in the renal proximal tubules. Here, we demonstrate that megalin, a multifunctional endocytic receptor in the proximal tubular epithelium, mediates the uptake and degradation of PTH. Megalin was purified from kidney membranes as the major PTH-binding protein and shown in BIAcore analysis to specifically bind full-length PTH and amino-terminal PTH fragments (K d 0.5 M). Absence of the receptor in megalin knockout mice resulted in 4-fold increased levels of amino-terminal PTH fragments in the urine. In F9 cells expressing both megalin and the PTH/PTH-related peptide receptor (PTH/PTHrP receptor), uptake and lysosomal degradation of the hormone was mediated through megalin. Blocking megalin-mediated clearance of PTH resulted in 3-fold increased stimulation of the PTH/PTHrP receptor. These data provide evidence that megalin is involved in the renal catabolism of PTH and potentially antagonizes PTH/PTHrP receptor activity in the proximal tubular epithelium.

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Section: Resultsmentioning

confidence: 99%

Megalin Antagonizes Activation of the Parathyroid Hormone Receptor

Hilpert¹,

Nykjaer²,

Jacobsen³

et al. 1999

Journal of Biological Chemistry

110

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“…Also, pulsatile administration of PTH (1-34) doubled the fractional intestinal absorbance of calcium over baseline, whereas continuous administration had no effect (Podbesek et al, 1983). The down-regulation of the PTH receptor after continuous PTH administration may explain the divergent behavior of these two forms of administration (Mahoney et al, 1983).…”

Section: Fundamentals Of Bone Remodelingmentioning

confidence: 99%

Parathyroid Hormone Temporal Effects on Bone Formation and Resorption

Kroll

2000

Bulletin of Mathematical Biology

117

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Parathyroid hormone (PTH) paradoxically causes net bone loss (resorption) when administered in a continuous fashion, and net bone formation (deposition) when administered intermittently. Currently no pharmacological formulations are available to promote bone formation, as needed for the treatment of osteoporosis. The paradoxical behavior of PTH confuses endocrinologists, thus, a model bone resorption or deposition dependent on the timing of PTH administration would de-mystify this behavior and provide the basis for logical drug formulation. We developed a mathematical model that accounts for net bone loss with continuous PTH administration and net bone formation with intermittent PTH administration, based on the differential effects of PTH on the osteoblastic and osteoclastic populations of cells. Bone, being a major reservoir of body calcium, is under the hormonal control of PTH. The overall effect of PTH is to raise plasma levels of calcium, partly through bone resorption. Osteoclasts resorb bone and liberate calcium, but they lack receptors for PTH. The preosteoblastic precursors and preosteoblasts possess receptors for PTH, upon which the hormone induces differentiation from the precursor to preosteoblast and from the preosteoblast to the osteoblast. The osteoblasts generate IL-6; IL-6 stimulates preosteoclasts to differentiate into osteoclasts. We developed a mathematical model for the differentiation of osteoblastic and osteoclastic populations in bone, using a delay time of 1 hour for differentiation of preosteoblastic precursors into preosteoblasts and 2 hours for the differentiation of preosteoblasts into osteoblasts. The ratio of the number of osteoblasts to osteoclasts indicates the net effect of PTH on bone resorption and deposition; the timing of events producing the maximum ratio would induce net bone deposition. When PTH is pulsed with a frequency of every hour, the preosteoblastic population rises and decreases in nearly a symmetric pattern, with 3.9 peaks every 24 hours, and 4.0 peaks every 24 hours when PTH is administered every 6 hours. Thus, the preosteoblast and osteoblast frequency depends more on the nearly constant value of the PTH, rather than on the frequency of the PTH pulsations. Increasing the time delay gradually increases the mean value for the number of osteoblasts. The osteoblastic population oscillates for all intermittent administrations of PTH and even when the PTH infusion is constant. The maximum ratio of osteoblasts to osteoclasts occurs when PTH is administered in pulses of every 6 hours. The delay features in the model bear most of the responsibility for the occurrence of these oscillations, because without the delay and in the presence of constant PTH infusions, no oscillations occur. However, with a delay, under constant PTH infusions, the model generates oscillations. The osteoblast oscillations express limit cycle behavior. Phase plane analysis show simple and complex attractors. Subsequent to a disturbance in the number of osteoblasts, the osteoblasts quickly regain t...

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“…PTH tonic secretory rate in the GC-treated group was approximately half of the control group, whereas fractional pulsatile PTH secretion was more than doubled (with reduced intervals between peaks) in the GC-treated vs. control groups (P = < 0.01). 42 These abnormalities in PTH secretory dynamics may strengthen the concept that the modality of administration of exogenous PTH is critical for its biological actions and should mimic by the extent that is pharmacologically possible its physiological pattern of secretion [37][38][39][40][41] and give an insight into the efficacy of exogenous intermittent PTH treatment in GIOP. 43 In fact, this redistribution of spontaneous PTH secretion may be interpreted as a compensatory, though inadequate, response to chronic GC excess triggered by low circulating levels of vitamin D or by signals generated from bone such as RANKL-OPG and IGF-I in which GC and PTH have diametrically opposite effects.…”

Section: Effect Of Glucocorticoids On Pulsatile Pth Secretionmentioning

confidence: 86%