Open AccessActivation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways
Author(s) -
Ming-Wei Wang,
Zhao Yang,
Xu Chen,
Shuhua Zhou,
Ge-Lin Huang,
Jianfei Sun,
Hui Jiang,
Wei Xu,
Haocheng Lin,
Xiao Yu,
Jing Sun
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2107363118
Subject(s) - epididymitis , orchitis , medicine , infertility , epididymis , male infertility , antibiotics , g protein coupled receptor , genitourinary system , receptor , bioinformatics , biology , pathology , surgery , microbiology and biotechnology , sperm , pregnancy , genetics , andrology
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 β-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.