Differential effects of intermittent PTH(1–34) and PTH(7–34) on bone microarchitecture and aortic calcification in experimental renal failure
Introduction
Disturbances of bone and mineral metabolism are well recognized features of chronic kidney disease (CKD) [1], [2]. Vascular calcification and ectopic calcification of other soft tissues are commonly observed. These actions on mineral metabolism in patients with CKD are accompanied by increased synthesis, secretion and circulating levels of parathyroid hormone (PTH) and PTH fragments, which lead to the development of secondary hyperparathyroidism (SHPT) [3], [4]. The factors involved in the pathogenesis of SHPT in CKD, include phosphate retention, low 1,25(OH)2D3 and vitamin D receptors, decreased serum free calcium and parathyroid calcium-sensing receptors [5], [6], downregulation of PTH receptors [7], [8], [9], [10], and the accumulation of uremic toxins and acidosis [9], [11] that contribute to skeletal resistance to the actions of PTH and a spectrum of bone diseases collectively called osteodystrophy. Although the mechanism of resistance is incompletely understood, uremic patients require PTH levels 2–3 times normal to maintain bone turnover [56]. Excessive suppression of PTH secretion, however, may lead to low bone turnover, so-called adynamic bone disease [12], [13].
The type I PTH receptor (PTH1R) is the predominant form expressed in bone and kidney and is a member of class B of the superfamily of G protein-coupled receptors (GPCRs) [14], [15]. It mediates the actions of PTH and of PTH fragments containing an intact amino terminus. In the kidney, the PTH1R mediates the regulation of PTH on the renal transport of phosphate and calcium [16]. In renal tubular epithelial cells, signal and expression of PTH1R appears to be modulated in a cell-specific manner. Mounting evidence supports the view that in renal failure serum PTH(7–84) accumulates to high levels [17], [18] that may approach those of PTH(1–84) [18], [19], [20]. It has been suggested that the competitive inhibition of PTH1R binding by amino-truncated PTH fragments contributes to the PTH resistance of uremia [21]. However, as indicated above, PTH1R downregulation has been described in the same pathological setting [7], [22], which is inconsistent with the view that PTH(7–34) acts exclusively as an antagonist.
Recent work shows that PTH(7–84) and its synthetic analog, PTH(7–34), internalize [23], [24] and downregulate [25] the PTH1R without antecedent or concomitant receptor activation, whereas PTH(1–34) promotes synchronized PTH1R activation and internalization. This phenomenon occurs in a cell-specific manner that depends on the expression of the scaffolding protein Na/H exchange regulatory factor (NHERF1) [23], [26], a cytoplasmic adaptor that interacts with the carboxy-terminus of the PTH1R and is implicated in protein targeting and in the assembly of protein complexes [26], [27]. These findings provide a plausible alternative explanation for PTH1R downregulation and resistance in renal failure. According to this hypothesis, PTH(7–84) may contribute to hormone resistance by inducing PTH1R internalization and downregulation without accompanying activation. Reducing the number of plasma membrane-delimited PTH receptors would diminish the action of full-length or amino-terminal PTH fragments.
Other studies addressed competitive interactions between amino-truncated PTH fragments and PTH(1–34) or PTH(1–84) [28], [29]. PTH(7–34) induces PTH1R internalization on its own and is only a competitive inhibitor at higher concentrations [23]. In the present study, we used exogenous PTH(1–34) and the amino-truncated peptide PTH(7–34) in animal models of CKD without secondary hyperparathyroidism to test the hypothesis that amino-truncated PTH fragments downregulate the PTH1R, thereby reducing bone demineralization and vascular calcification.
Section snippets
Animals and experimental protocol
All experiment protocols were approved by the University of Pittsburgh Institutional Animal Care and Use Committee (IACUC).
Nine-week old male Wistar rats weighing 250–300 g, were purchased from Charles River Laboratories. Animals were fed standard diet (LabDiet, PMI Nutrition LLC, MO, US) containing 1.0% calcium, 0.75% phosphorus and 22.5% protein. The animals were allowed free access to food and water and housed in individual cages at constant room temperature with a 12-h light and dark cycle.
Results
All animals gained weight from the time of entry in the protocol. Rats undergoing PTX gained as much weight as Sham animals. However, rats subjected to NPX or PTX/NPX gained significantly less weight (83% and 73% compared to Sham; P < 0.05, P < 0.01, respectively).
Discussion
The present studies were designed to analyze and compare the effects of intermittent PTH(1–34) or PTH(7‑34) treatment on bone microarchitecture, vascular calcification, and PTH1R expression in an animal model of experimental renal failure. It has been reported that the administration of PTH prevents osteoporotic fractures in postmenopausal women, improves fracture healing and implant fixation, and osteogenesis in model animals [37], [38], [39], [40]. We show here that in an animal model of
Acknowledgments
This work was supported by grant DK 54171 (PAF) and by a Minority Supplement (EMS) from the National Institutes of Health, an internal award from the Office of the Senior Vice Chancellor for the Health Sciences, University of Pittsburgh (EMS) and The Carl L. Nelson Chair of Orthopaedic Surgery (LJS). The authors thank Dr. Nathalie Taesch, who helped with vascular histology and staining.
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