Activation of PTH1R alleviates epididymitis and orchitis through Gq and beta-arrestin-1 pathways.

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Citation

Wang MW, Yang Z, Chen X, Zhou SH, Huang GL, Sun JN, Jiang H, Xu WM, Lin HC, Yu X, Sun JP

Activation of PTH1R alleviates epididymitis and orchitis through Gq and beta-arrestin-1 pathways.

Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2107363118. doi: 10.1073/pnas.2107363118.

PubMed ID
34740971 [ View in PubMed
]
Abstract

Inflammation in the epididymis and testis contributes significantly to male infertility. Alternative therapeutic avenues treating epididymitis and orchitis are expected since current therapies using antibiotics have limitations associated to side effects and are commonly ineffective for inflammation due to nonbacterial causes. Here, we demonstrated that type 1 parathyroid hormone receptor (PTH1R) and its endogenous agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP), were mainly expressed in the Leydig cells of testis as well as epididymal epithelial cells. Screening the secretin family G protein-coupled receptor identified that PTH1R in the epididymis and testis was down-regulated in mumps virus (MuV)- or lipopolysaccharide (LPS)-induced inflammation. Remarkably, activation of PTH1R by abaloparatide (ABL), a Food and Drug Administration-approved treatment for postmenopausal osteoporosis, alleviated MuV- or LPS-induced inflammatory responses in both testis and epididymis and significantly improved sperm functions in both mouse model and human samples. The anti-inflammatory effects of ABL were shown to be regulated mainly through the Gq and beta-arrestin-1 pathway downstream of PTH1R as supported by the application of ABL in Gnaq(+/-) and Arrb1(-/-) mouse models. Taken together, our results identified an important immunoregulatory role for PTH1R signaling in the epididymis and testis. Targeting to PTH1R might have a therapeutic effect for the treatment of epididymitis and orchitis or other inflammatory disease in the male reproductive system.

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