Parathyroid hormone (PTH) regulates calcium metabolism and bone strength. Chronic kidney disease (CKD) leads to secondary hyperparathyroidism (SHP) which increases morbidity and mortality. High PTH expression in SHP is due to increased PTH mRNA stability mediated by changes in PTH mRNA interaction with stabilizing AUF1 and destabilizing KSRP. Pin1 isomerizes target proteins, including mRNA binding proteins. In SHP, Pin1 isomerase activity is decreased and phosphorylated KSRP fails to bind PTH mRNA, resulting in high PTH mRNA stability and levels. The molecular mechanisms underlying Pin1 regulation and their effect to increase PTH expression are unknown. We show by mass-spectrometry (MS) the CKD induced changes in rat parathyroid proteome and phosphoproteome profiles. Parathyroid Pin1 Ser16 and Ser71 phosphorylation, that disrupts Pin1 activity, is enhanced in acute and chronic kidney failure rats. Accordingly, pharmacologic Pin1 inhibition increases PTH expression in parathyroid organ cultures and transfected cells, through the PTH mRNA protein binding cis element and KSRP phosphorylation. Therefore, CKD leads to parathyroid loss of Pin1 activity by inducing Pin1 phosphorylation. This predisposes parathyroids to increase PTH production through modified PTH mRNA-KSRP interaction that is dependent on KSRP phosphorylation. CKD induced Pin1 and KSRP phosphorylation and the Pin1-KSRP-PTH mRNA axis thus drive secondary hyperparathyroidism.

No abstract

No abstract