Abnormal Accumulation of Collagen Type I Due to the Loss of Discoidin Domain Receptor 2 (Ddr2) Promotes Testicular Interstitial Dysfunction.
Abnormal Accumulation of Collagen Type I Due to the Loss of Discoidin Domain Receptor 2 (Ddr2) Promotes Testicular Interstitial Dysfunction.
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由于盘状蛋白结构域受体 2 (Ddr2) 缺失导致 I 型胶原蛋白异常积聚促进睾丸间质功能障碍
DOI：
10.1371/journal.pone.0131947
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhang YQ
中科院分区：
文献类型：
--
作者：
Zhu CC;Tang B;Su J;Zhao H;Bu X;Li Z;Zhao J;Gong WD;Wu ZQ;Yao LB;Li W;Zhang YQ
盘状结构域受体2（Ddr 2）功能等位基因的缺失导致老年雄性Ddr 2slie/slie小鼠睾丸间质细胞对促黄体激素（LH）的反应受损、睾酮产生降低和精子发生停滞。然而，负责这种表型的潜在机制仍然未知。在此，我们首次报道了Ddr2同源配体，即I型胶原蛋白（COL 1）的表达失调，可能是Ddr2 slie/slie突变睾丸中睾丸类固醇生成中断的原因。方法/主要发现Ddr2的表达沿着出生后的发育逐渐增加，而COL 1的表达从成年开始变得可以忽略不计。然而，在Ddr2 slie/slie突变体睾丸中，与Ddr2的不可检测的染色相反，COL 1表达不断检测到，在成年期检测到最高值。在实验输精管结扎模型中，Ddr2 slie/slie突变小鼠比野生型小鼠表现出早期雄激素缺乏，沿着纤维化组织在睾丸中的积累。在功能上，在更高浓度的COL 1处理的存在下，内源性Ddr2的消融导致TM 3细胞中睾酮（T）水平的显著降低。相反，Ddr2的过表达可以帮助TM 3细胞维持正常的睾丸类固醇合成，即使在高浓度的COL 1的存在下。此外，Ddr2的减弱表达与人类病理睾丸中血清T水平的失调水平相关。结论Ddr2 slie/slie突变睾丸组织间质COL 1异常积聚可能是导致睾丸激素合成功能障碍的原因。
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. Methodology/Principal Findings 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.
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DOI：
10.3109/08977194.2011.595714
发表时间：
2011-10
期刊：
Growth factors (Chur, Switzerland)
影响因子：
--
作者：
Biernacka A;Dobaczewski M;Frangogiannis NG
通讯作者：
Frangogiannis NG
影响因子：
2.1
作者：
JAROW, JP;GOLUBOFF, ET;MARSHALL, FF
通讯作者：
MARSHALL, FF
影响因子：
4.8
作者：
Odet, Fanny;Verot, Adelie;Le Magueresse-Battistoni, Brigitte
通讯作者：
Le Magueresse-Battistoni, Brigitte
影响因子：
3.8
作者：
Qu, Ning;Terayama, Hayato;Itoh, Masahiro
通讯作者：
Itoh, Masahiro
影响因子：
2.5
作者：
Diaz, ES;Pellizzari, E;Denduchis, B
通讯作者：
Denduchis, B