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Abnormal Accumulation of Collagen Type I Due to the Loss of Discoidin Domain Receptor 2 (Ddr2) Promotes Testicular Interstitial Dysfunction

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 Ddr2(slie/slie) mice. However, the underlying mechanism responsible for this pheno...

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Detalles Bibliográficos
Autores principales: Zhu, Chu-chao, Tang, Bin, Su, Jin, Zhao, Hu, Bu, Xin, Li, Zhen, Zhao, Jie, Gong, Wei-dong, Wu, Zhi-qun, Yao, Li-bo, Li, Wei, Zhang, Yuan-qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497730/
https://www.ncbi.nlm.nih.gov/pubmed/26158267
http://dx.doi.org/10.1371/journal.pone.0131947
Descripción
Sumario: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 Ddr2(slie/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 Ddr2(slie/slie) mutant testes. METHODOLOGY/PRINCIPAL FINDINGS: Expression of Ddr2 increased gradually along postnatal development, whereas COL1 expression became negligible from adulthood onwards. In Ddr2(slie/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, Ddr2(slie/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 Ddr2(slie/slie) mutant testes.