Parathyroid Cell Proliferation

HPT is invariably associated with an increased mass of parathyroid parenchyma. The parenchymal cell weight, however, may only be marginally elevated, and hypercalcemia can be alleviated by excision of pathologic glands weighing less than the normal parathyroid tissue of an individual. These findings suggest that deranged secretory regulation rather than increased cell mass is the principal cause of elevated serum PTH levels and hypercalcemia of HPT. Indeed, it has been suggested that a primary mutation increasing the secretory set-point might initiate and stimulate cell proliferation and that this stimulation declines when plasma calcium settles at the genomically determined level.79 Increased cell mass nevertheless may determine the portion of PTH secretion not suppressible by calcium,80 whereby hypercalcemia might be related to a complex mixture of increases in cell number and rates of hormone secretion per cell. Parathyroid cell turnover is normally very low, and the cells can be triggered to leave the quiescent G0 stage by hypocalcemia and calcitriol deficiency.27,81 These findings may be clinically relevant because reduced calcitriol levels are characteristically found even in subclinical disturbances of renal function. This circumstance also includes many elderly patients, who seem to display an unusual propensity for the development of primary HPT, especially in climates associated with limited sun exposure.77,82 Parathyroid cells in culture display gradually increasing calcium insensitivities of Ca2+ and PTH release, which develop in parallel to enhanced proliferation.27 Calcitriol inhibits proliferation but not hypertrophy and functional dedifferentiation of cultured cells. Hitherto unidentified factors in the circulation may interact in this coupling of function to proliferation because serum-free culture abolishes hyperplasia and decreased calcium sensitivity of cultured cells.83 In this context, it is interesting to note that a mitogenic factor with ability to stimulate parathyroid cell replication has been reported in the plasma of patients with MEN 1,84

The MEN1 gene has been mapped to chromosome 11 q 13 and might encompass the cell-signaling phospholipase Cp3.85 The constitutional mutation of this dominantly inherited disease is unmasked by loss of the wild-type allele, which suggests that tumorigenesis is related to inactivation of a tumor suppressor gene at the MEN1 locus.86 Similar allelic losses have also been found in subsets of sporadic parathyroid adenomas and consequently may represent important promoters of parathyroid growth.87 Rearrangements of the PTH gene and overexpression of the protooncogene PRAD1 on chromosome 1 lql3 have been identified primarily in large parathyroid adenomas.88,89 The PRAD1 gene encodes cyclin Dl, which is important in the G,-S phase transition that commits cells to divide.90 Consistent with findings of X-chromosome inactivation analysis,91 unequivocally enlarged MEN 1 lesions and a major proportion of sporadic parathyroid adenomas are monoclonal tumors, which may nevertheless develop polyclonal hyperplasia.92,93 In the multiglandular parathyroid involvement of sporadic and MEN 1-associated primary HPT, there is considerable variation in expression of the 500-kd calcium sensor protein. This phenotypic variation is particularly striking between chief cell nodules of individual glands67,94 and indicates that such homogeneously appearing nodules may represent individual cell clones. Hyperplastic parathyroid tissue has not been found to display a monoclonal pattern upon analysis of restriction fragment length polymorphisms.91 This circumstance, however, does not exclude the presence of multiple monoclonal lesions, which indeed has been suggested by analysis of X-chromosome inactivation.95 Similarly, the characteristically multiglandular and asymmetric parathyroid enlargement in uremic HPT may represent both monoclonal and polyclonal components together with complex admixtures of vitamin D deficiency and parathyroid vitamin D resistance. Indeed, the larger nodules from patients with hypercalcemia of uremic HPT have displayed clonal allelic losses involving the MEN1 gene on chromosome ll.96 Parathyroid carcinomas, but not adenomas, have also revealed allelic losses of the retinoblastoma gene,97 and increased expression of protooncogenes c-myc and c-fos has been associated with parathyroid cell proliferation.98 It has been demonstrated that sporadic parathyroid carcinomas frequently possess mutations of the HRPT2 gene, which encodes the parfibromin protein, and that these HRPT2 mutations have pathogenetic implications.99 These and hitherto unrecognized secondary genomic alterations may contribute to the appearance of complex and heterogeneous characteristics upon analysis of pathologic parathyroid tissue and highlight the limitations in our current knowledge about the causes and pathogenetic mechanisms contributing to parathyroid growth and secretory derangements in HPT.

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