Integrated transcriptomic and proteomic analyses for the characterization of parathyroid oxyphil cells in uremic patients

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency

“…The absence of a purely mitochondrial signature in all oxyphils regardless of tissue source argues against compensatory mitochondrial biogenesis caused by mitochondrial mutations ( 25 ) in our vitamin D-deficient cohort. In contrast to the divergent chief vs oxyphil signatures observed in the hyperplastic glands of SHPT patients ( 16 ), the high degree of transcriptional similarity between chief and oxyphil cells within individual parathyroid glands in our study suggests that vitamin D deficiency exerts the same effect on both cell types in parathyroid adenomas. The fact that oxyphil and chief cells share expression of definitive parathyroid markers and retain highly similar transcriptomic profiles that respond similarly to vitamin D deficiency is consistent with oxyphils being a derivative of chief cells.…”

“…The increased oxyphilic content of Def-Ts is reminiscent of reports characterizing the hyperplastic parathyroid glands of patients with chronic kidney disease who have developed secondary hyperparathyroidism (SHPT) ( 11–13 , 16 ). In the most recent of these studies, Mao and coworkers compared chief and oxyphil cell nodules from the parathyroid glands of uremic SHPT patients and found that the oxyphil cells were enriched for mitochondrial proteins; expressed lower levels of proliferation-associated genes and regulatory factors such as the vitamin D receptor, Klotho, and CaSR; and secreted higher levels of PTH ( 16 ). This cellular phenotype is similar to Def-Ts, where mitochondrial genes are upregulated in the absence of a proliferative signature, and higher PTH secretion is observed relative to Rep-T patients.…”

“…Parathyroid oxyphils are characterized by high mitochondrial content and appear more abundant in older individuals ( 13 ), but the origin and physiological functions of these cells are unknown. Previously, we and others have shown that similar to chief cells, parathyroid oxyphil cells can respond to extracellular calcium stimulation via calcium sensing receptor (CaSR)-dependent signal transduction ( 14 ), express multiple parathyroid-specific factors including GCM2 and PTH ( 11 , 15 ), and contain key regulatory factors such as the vitamin D-receptor, Klotho, and mitochondrial components involved in cellular respiration ( 16 ). Because oxyphil-dominant parathyroid tumors appear to drive biochemically more severe disease presentation in PHPT ( 17–21 ) and oxyphilic hyperplasia is associated with the loss of calcimimetic responsiveness in SHPT ( 12 ), we hypothesized that chronic 25OHD deficiency could produce changes in parathyroid oxyphil content and gene expression that reduce calcium sensitivity, increase PTH hypersecretion, and promote adenoma development in PHPT.…”

Identification of key biomarkers based on the proliferation of secondary hyperparathyroidism by bioinformatics analysis and machine learning

“…Our previous retrospective analysis showed that mitochondrial mass and the mitochondrial-associated protein in oxyphil cell nodules are increased compared to those in chief cell nodules. Moreover, the synthesis and secretion of PTH in oxyphil cell nodules were significantly higher than in chief cell nodules ( Mao et al, 2022 ). Therefore, PCOLCE2 may be related to the mitochondria of the parathyroid gland in SHPT patients.…”