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KMT2A-driven cyclin D2 upregulation and chronic inflammation as potential drivers of sporadic parathyroid adenoma pathogenesis

ABSTRACT: Sporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, but the mechanisms involved in its pathogenesis remain incompletely understood. Here we present a single-cell transcriptomic atlas detailing the cellular differences between human PA and normal parathyroid gland (PG) tissues and delineating the transcriptome of individual cell types. We show that there is a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells (PGCs), with transcriptional upregulation of cyclin D2 driven by the transcriptional coactivator, histone-lysine N-methyltransferase 2A (KMT2A) through the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3) potentially involved in promoting PAC proliferation. Moreover, we demonstrate that PA tissues are heavily infiltrated with myeloid cells, and that fibroblasts, endothelial cells (ECs), as well as macrophages in the PA microenvironment are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues. Collectively, these results provide new insights into the etiology of PA, where the pathogenesis likely involves the net contribution of the dysregulated KMT2A-STAT3/GATA3-cyclin D2 axis in PACs and the chronic inflammation of the microenvironment. These findings provide practical implications for the treatment of PA through KMT2A targeting and anti-inflammation therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190773 | GEO | 2024/05/01

REPOSITORIES: GEO

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Project description:Guava Psidium guajava L (Pg) and bhumi amla Phyllanthus amarus Schum. et Thonn (Pa) are well-known plants in traditional medicine. However, the capacity of these plants for improving the immune system of aquatic species has received less attention so far. This study aimed to investigate the effects of single supply or mixture of Pg and Pa extracts on immune responses, disease resistance and liver proteome profiles in striped catfish Pangasianodon hypophthalmus. Fish were fed diets including basal diet 0% or one of three doses of each plant extract, either alone or in mixture, 0.08, 0.2 or 0.5% Pg, Pa or mixture (Pg:Pa, v/v) for 6 weeks. The immune parameters (respiratory burst activity (RBA); nitric oxide synthase (NOS), total immunoglobulin, lysozyme and complement activities) were examined at W3, W6 post-feeding, and after challenge test. The growth parameters and the challenge test with Edwardsiella ictaluri were done at W6. The liver proteome profiles were analysed in W6 at 0.08% and 0.5% of each extract. The results showed that extract-based diets significantly improved growth parameters in the Pg0.2 group compared to control. The cellular immune responses in spleen and the humoral immune responses in plasma were significantly improved in a dose and time-dependent manner. Diets supplemented with single Pg and Pa extracts, and to lesser extent to combined extracts, could significantly decrease the mortality of striped catfish following bacterial infection compared to control. The proteomic results indicated that some pathways related to immune responses, antioxidant and lipid metabolism were enriched in liver at W6. Several proteins (i.e., CD8B, HSP90AA1, HSP90AB1, PDIA3, CASP8, TUBA1C, CCKAR, GNAS, GRIN2D, PLCG1, PRKCA, SLC25A5, VDAC2, ACTN4, GNAI2, LCK, CARD9, NLRP12, and NLRP3) were synergistically upregulated in mixture of Pg and Pa-based diets compared to control and single dietary treatments. Taken together, the results revealed that single Pg and Pa extracts at 0.2 and 0.5% and their mixture at 0.08 and 0.5% have the potential to modulate the immune mechanisms and disease resistance of striped catfish. Moreover, the combination of Pg and Pa in diets suggested positive synergistic effects liver proteome profile related to immune system processes.

Project description:The pathogenesis of primary hyperparathyroidism (I-HPT) and secondary hyperparathyroidism (II-PTH) remains to be elucidated. To characterize their pathophysiology, we investigated the effects of calcium and phosphate on cell proliferation and PTH release in an organ culture of parathyroid tissues. Dissected parathyroid tissues obtained from patients with I-HPT (adenoma) or II-PTH (nodular hyperplasia) were precultured on a collagen-coated membrane for 1-4 week. After exchanging the medium for one containing various concentrations of phosphate, PTH release and [3H]thymidine incorporation were studied. In contrast to dispersed parathyroid cells cultured in a monolayer, calcium decreased PTH release in a concentration-dependent manner in parathyroid tissues. Furthermore, when parathyroid tissues obtained from II-PTH were precultured for 1-4 weeks, PTH release and parathyroid cell proliferation were significantly increased in high-phosphate medium. These phosphate effects were also observed to a lesser extent in parathyroid tissues obtained from I-HPT, but there was no significant difference between I-HPT and II-HPT. Microarray analyses revealed that mRNA levels of PTH, CaSR, and VDR were well preserved, and several growth factors (e.g. TGF-beta1-induced protein) were abundantly expressed in II-PTH. Using organ cultures of hyperparathyroid tissues, in which PTH release and CaSR are well preserved for a prolonged period, we have demonstrated that phosphate stimulates parathyroid cell proliferation not only in II-PTH but also in I-HPT. Although the mechanism responsible for phosphate-induced cell proliferation remains to be elucidated, our in vitro findings suggest that both parathyroid tissues preserve to some extent a physiological response system to hyperphosphatemia as observed in normal parathyroid cells. These data will be published in Journal of Bone & Mineral Metabolism. Experiment Overall Design: Two conditioned experimets, low vs. high phosphate medium, cultured for 1 and 4 days

Project description:The pathogenesis of primary hyperparathyroidism (I-HPT) and secondary hyperparathyroidism (II-PTH) remains to be elucidated. To characterize their pathophysiology, we investigated the effects of calcium and phosphate on cell proliferation and PTH release in an organ culture of parathyroid tissues. Dissected parathyroid tissues obtained from patients with I-HPT (adenoma) or II-PTH (nodular hyperplasia) were precultured on a collagen-coated membrane for 1-4 week. After exchanging the medium for one containing various concentrations of phosphate, PTH release and [3H]thymidine incorporation were studied. In contrast to dispersed parathyroid cells cultured in a monolayer, calcium decreased PTH release in a concentration-dependent manner in parathyroid tissues. Furthermore, when parathyroid tissues obtained from II-PTH were precultured for 1-4 weeks, PTH release and parathyroid cell proliferation were significantly increased in high-phosphate medium. These phosphate effects were also observed to a lesser extent in parathyroid tissues obtained from I-HPT, but there was no significant difference between I-HPT and II-HPT. Microarray analyses revealed that mRNA levels of PTH, CaSR, and VDR were well preserved, and several growth factors (e.g. TGF-beta1-induced protein) were abundantly expressed in II-PTH. Using organ cultures of hyperparathyroid tissues, in which PTH release and CaSR are well preserved for a prolonged period, we have demonstrated that phosphate stimulates parathyroid cell proliferation not only in II-PTH but also in I-HPT. Although the mechanism responsible for phosphate-induced cell proliferation remains to be elucidated, our in vitro findings suggest that both parathyroid tissues preserve to some extent a physiological response system to hyperphosphatemia as observed in normal parathyroid cells. These data will be published in Journal of Bone & Mineral Metabolism. Keywords: Organ culture experiments, dultured in low vs.high phosphate medium

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KMT2A-driven cyclin D2 upregulation and chronic inflammation as potential drivers of sporadic parathyroid adenoma pathogenesis

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