Nodular parathyroid growth: role of vitamin D resistance.

The parathyroid gland is a low turnover, discontinugrowth [6]. Similar to parathyroid adenomas in humans, ously replicating tissue composed of cells that rarely unthese mice slowly develop large hyperplastic glands and dergo mitoses [1, 2]. The quiescent parathyroid cells, in some cases adenomatous glands. However, in nodular however, retain their potential to divide in response to hyperplasia in humans, different from parathyroid adegrowth stimuli, including the onset of renal failure, low nomas, no correlation exists between levels of cyclin D1 calcium, high phosphorus, or vitamin D deficiency [2]. and mitogenic activity. More important, these studies in In patients with renal failure, parathyroid glands initially mice [6] and recent studies in uremic rats [7] also indigrow diffusely and polyclonally. In advanced stages of cated that reduced CaSR in the parathyroid glands folparathyroid hyperplasia, the cells in the nodules translowed rather than caused the hyperplasia. form monoclonally and proliferate aggressively [3]. NodStudies by Tokumoto et al [8], in this issue of Kidney ular hyperplasia constitutes the more severe form of International, present the impaired induction of the exsecondary hyperparathyroidism. Neither the mechapression of the cyclin-dependent kinase inhibitors p21 nisms triggering the initial increase in proliferating activand p27 by the VDR as a pathogenic mechanism for ity nor those resulting in changes in growth pattern are nodular parathyroid growth in renal failure. Examinacompletely elucidated. tion of nodular hyperplastic parathyroid tissue from 23 Recent studies in 5/6 nephrectomized rats have implipatients demonstrated a strong direct correlation becated elevations of transforming growth factor-alpha tween VDR levels and parathyroid content of the cyclin(TGF) expression in the increased proliferating activdependent kinase inhibitors p21 and p27. More impority of parathyroid cells in early renal failure [4]. High tant, the lower the parathyroid levels of VDR and cyclindietary phosphorus intake further enhances parathyroid dependent kinase inhibitors, the higher the markers of levels of TGFand therefore, proliferation rates [4]. proliferating activity and the size of the nodular gland. Prevention of the increases in TGFand induction of The lack of an association between parathyroid levels parathyroid levels of the cyclin-dependent kinase inhibiof p21 and p53, the main regulator of p21 expression, tor p21 by high dietary calcium, phosphorus restriction, suggested a direct induction of p21 by the VDR as a or vitamin D therapy mediate their effects in attenuating potential mechanism. The lack of a parathyroid cell line or completely counteracting the growth-promoting sigand the diffuse pattern of parathyroid hyperplasia in nals triggered by uremia [4, 5]. The relative contribution uremic rats, however, prevent from conclusive validation of either mechanism to arrest parathyroid growth reof the proposed model, which emerges solely from simulmains unclear. taneous assessment of parathyroid expression of VDR High calcium and vitamin D are efficient in controlling and cell-cycle regulators in nodular human parathyroid parathyroid levels of TGFand its downstream-growth glands. Nevertheless, the findings by Tokumoto et al signal, cyclin D1, in an experimental model of early urefurther our understanding on the pathogenesis of the mia [5]. This finding suggests a role for the progressive abnormalities in parathyroid cell replication that could reduction in the levels of the calcium-sensing receptor help improve therapeutic strategies to avoid the more (CaSR) and the vitamin D receptor (VDR) in the worssevere form of secondary hyperparathyroidism. Their ening of proliferating activity in patients with advanced results support the findings from studies in early uremia renal failure. In fact, higher cyclin D1 expression occurs in rats on the importance of vitamin D induction of in nodular hyperplasia compared to diffuse hyperplastic parathyroid p21 expression in regulating the rate of paraglands [3]. However, neither the increase in cyclin D1 thyroid cell proliferation [5]. In addition to confirming expression nor the reduction in CaSR is a key determithe association between a reduction in p27 and hypernant of the switch to the more aggressive nodular growth. plastic growth in secondary hyperparathyroidism [9], Studies in transgenic mice targeted to specifically overextheir demonstration of vitamin D-dependent regulation press cyclin D1 in the parathyroids conclusively demonof p27 in the parathyroids suggests an additional mechastrated the importance of cyclin D1 in parathyroid nism for the resistance to the antiproliferative effects of the sterol in nodular hyperplasia. In aggressive carcinomas, where growth is driven exclusively by TGFactiva