Parathyroid hyperplasia in chronic renal failure: role of calcium, phosphate, and calcitriol.

Abstract

tissue is constantly associated with hypersecretion of days [10–12]. One culture model has been described, parathyroid hormone (PTH) [1–3]. The increase in using bovine parathyroid cell organoids which mainparathyroid cell mass is mainly due to enhanced paratained the ability to modulate PTH secretion in thyroid cell proliferation, resulting in increased cell response to extracellular Ca2+ [Ca2+e] and tissue-like numbers, whereas cell hypertrophy appears to play morphology for 2 weeks in culture [13]. However, only only a minor role, if any [3]. Whether a modified rate one long-term study of bovine parathyroid cells demof parathyroid cell apoptosis also contributes to the onstrated a release of bioactive bovine PTH but with hyperplasia is still a matter of debate [2–4]. reduced sensitivity to calcium [14]. It has been demonThe mode of parathyroid cell proliferation is almost strated by others that the reduced responsiveness of certainly polyclonal in the initial stages of renal failure cultured bovine parathyroid cells to [Ca2+e] was associ[1]. However, in the more advanced stages with severe ated with a marked reduction in the expression of the secondary hyperparathyroidism (2-HPT), we [5] and Ca2+-sensing receptor (CaR) [15,16 ]. Other culture others [6 ] have shown that benign monoclonal tumours models which have been used were parathyroid-derived develop in a high proportion of parathyroid glands, cells with no PTH secretory capacity [17,18]. probably favoured by the existence of polyclonal paraWe have recently developed a functional human thyroid hyperplasia for many years [1]. Multiclonal parathyroid cell culture system capable of maintaining tumours may also form in some instances [3]. At the regulation of its secretory activity and the expression cellular level, the increase in parathyroid cell proliferaof extracellular CaR mRNA and protein for several tion in uraemic patients is accompanied by de novo weeks [19]. For this purpose, we have used parathyroid expression of TGF-a and strong expression of its cells derived from hyperplastic parathyroid tissue of receptor, EGF-R [7]. patients with severe uraemic 2-HPT. This choice was The factors primarily involved in the stimulation of made because hyperplastic parathyroid cells grew parathyroid tissue hyperplasia in chronic renal failure better than cells derived from normal parathyroid are not yet well understood. The generally abnormal glands. The achievement of relatively stable, albeit metabolism of calcium, phosphate, and vitamin D low-degree cellular proliferation might explain the probably plays an important part, as suggested by observed conservation of CaR expression, in contrast several recent studies in experimental animals [8,9]. to previous culture models. Thus a diet poor in calcium and/or vitamin D appears This culture model enables the conduction of to stimulate parathyroid cell proliferation. A diet poor detailed studies of the molecular mechanisms resin phosphate inhibits proliferation whereas a phosponsible for changes in gland sensitivity to [Ca2+e]. phate-rich diet stimulates it. Moreover, for the first time it allows the examination It is not known at present whether the effects of of the modulation of parathyroid cell growth in vitro calcium, phosphate, and vitamin D are direct or indirin a model which remains responsive to [Ca2+e] and ect. The main reason for this lack of knowledge is that to study in particular factors directly involved in no suitable in vitro model has been available which parathyroid cell proliferation and apoptosis. Whereas would allow the performance of an in-depth study of direct effects on the parathyroid gland in terms of PTH the impact of these factors. Available cell culture synthesis and/or secretion have been convincingly demsystems do not usually permit the maintainance of onstrated for calcium and calcitriol [20], and more functionally active parathyroid cells for a long period: recently for phosphate [21–23], the hypothesis of direct present culture systems are characterized by a rapid action of these three factors on parathyroid tissue