2. Academic Validation
  3. Activation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways

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

  • Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2107363118. doi: 10.1073/pnas.2107363118.
Ming-Wei Wang 1,  Zhao Yang 1,  Xu Chen 2,  Shu-Hua Zhou 2,  Ge-Lin Huang 3,  Jian-Ning Sun 2,  Hui Jiang 4,  Wen-Ming Xu 5,  Hao-Cheng Lin 6,  Xiao Yu 7,  Jin-Peng Sun 8 9
Affiliations

Affiliations

  • 1 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong 250012, China.
  • 2 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong 250012, China.
  • 3 Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
  • 4 Department of Urology, Peking University Third Hospital, Beijing 100191, China.
  • 5 Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China; sunjinpeng@sdu.edu.cn yuxiao@sdu.edu.cn haochenglin292@163.com xuwenming@scu.edu.cn.
  • 6 Department of Urology, Peking University Third Hospital, Beijing 100191, China; sunjinpeng@sdu.edu.cn yuxiao@sdu.edu.cn haochenglin292@163.com xuwenming@scu.edu.cn.
  • 7 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong 250012, China; sunjinpeng@sdu.edu.cn yuxiao@sdu.edu.cn haochenglin292@163.com xuwenming@scu.edu.cn.
  • 8 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong 250012, China; sunjinpeng@sdu.edu.cn yuxiao@sdu.edu.cn haochenglin292@163.com xuwenming@scu.edu.cn.
  • 9 Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing 100091, China.
PMID: 34740971 DOI: 10.1073/pnas.2107363118
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 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.

Keywords

PTH1R; abaloparatide; epididymitis; mumps virus; orchitis.

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