title: Abnormal Accumulation of Collagen Type I Due to the Loss of Discoidin Domain Receptor 2 (Ddr2) Promotes Testicular Interstitial Dysfunction.
abstract: BACKGROUND
  Loss of functional allele for discoidin domain receptor 2 (Ddr2) results in impaired Leydig cell response to luteinizing hormone (LH), low testosterone production and arrested spermatogenesis in older male Ddr2slie/slie mice. However, the underlying mechanism responsible for this phenotype remains unknown. Herein, we reported for the first time that the deregulated expression of Ddr2 cognate ligand, namely collagen type I (COL1), may account for the disruption of the testicular steroidogenesis in Ddr2slie/slie mutant testes.
  
  
  RESULTS
  Expression of Ddr2 increased gradually along postnatal development, whereas COL1 expression became negligible from adulthood onwards. In Ddr2slie/slie mutant testis, however, in contrast to the undetectable staining of Ddr2, COL1 expression was constantly detected, with the highest values detected during adulthood. In the experimental vasectomy model, Ddr2slie/slie mutant mice exhibited an early androgen deficiency than wild-type mice, along with the accumulation of fibrotic tissue in the interstitium. Functionally, ablation of endogenous Ddr2 resulted in a significant decrease of testosterone (T) level in TM3 cells in the presence of higher concentration of COL1 treatment. Conversely, overexpression of Ddr2 could help TM3 cells to maintain a normal testicular steroidogenesis even in the presence of high concentration of COL1. Additionally, attenuated expression of Ddr2 correlates to the deregulated level of serum T levels in human pathological testes.
  
  
  CONCLUSIONS
  Abnormal accumulation of interstitial COL1 may be responsible for the steroidogenic dysfunction in Ddr2slie/slie mutant testes.
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Chu-chao
authors.initials: CC
authors.lastname: Zhu
authors.affiliation: Department of International Medical, China-Japan Friendship Hospital, Beijing 100029, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Bu
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Wei-dong
authors.initials: WD
authors.lastname: Gong
authors.affiliation: Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Zhi-qun
authors.initials: ZQ
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Li-bo
authors.initials: LB
authors.lastname: Yao
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yuan-qiang
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D004195:Disease Models, Animal; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D007985:Leydig Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009845:Oligospermia / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011863:Radioimmunoassay; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054331:Sertoli Cell-Only Syndrome / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000378:metabolism / Q000473:pathology*; D013739:Testosterone / Q000097:blood
chemical_list: D024042:Collagen Type I; D034741:RNA, Small Interfering; D011975:Receptors, Mitogen; D013739:Testosterone; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases