Conditional overexpression of TGF-β1 disrupts mouse salivary gland development and function

被引：77
作者：
Hall, Bradford E.
Zheng, Changyu [2 ]
Swaim, William D. [2 ]
Cho, Andrew [3 ]
Nagineni, Chandrasekharam N. [4 ]
Eckhaus, Michael A. [5 ]
Flanders, Kathleen C. [6 ]
Ambudkar, Indu S. [2 ]
Baum, Bruce J. [2 ]
Kulkarni, Ashok B. [1 ]
机构：
[1] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA
[2] Mol Physiol & Therapeut Branch, Bethesda, MD USA
[3] Natl Inst Dent & Craniofacial Res, Gene Targeting Facil, Bethesda, MD 20892 USA
[4] NEI, Immunol Lab, Bethesda, MD 20892 USA
[5] Off Res Serv, Diagnost & Res Serv Branch, Div Vet Resources, Bethesda, MD USA
[6] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA
来源：
LABORATORY INVESTIGATION | 2010年 / 90卷 / 04期
基金：
美国国家卫生研究院;
关键词：
transforming growth factor-beta; fibrosis; salivary glands; saliva; GROWTH-FACTOR-BETA; TGF-BETA; SJOGRENS-SYNDROME; TRANSGENIC MICE; SUBMANDIBULAR-GLAND; TRANSFORMING GROWTH-FACTOR-BETA-1; BRANCHING MORPHOGENESIS; ABNORMAL DISTRIBUTION; EXTRACELLULAR-MATRIX; IMMUNE-RESPONSES;
D O I：
10.1038/labinvest.2010.5
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
Transforming growth factor-beta (TGF-beta) signaling is known to affect salivary gland physiology by influencing branching morphogenesis, regulating ECM deposition, and controlling immune homeostasis. To study the role of TGF-beta 1 in the salivary gland, we created a transgenic mouse (beta 1(glo)) that conditionally overexpresses active TGF-beta 1 upon genomic recombination by Cre recombinase. beta 1(glo) mice were bred with an MMTV (mouse mammary tumor virus)-Cre (MC) transgenic line that expresses the Cre recombinase predominantly in the secretory cells of both the mammary and salivary glands. Although most of the double positive (beta 1(glo)/MC) pups die either in utero or just after birth, clear defects in salivary gland morphogenesis such as reduced branching and increased mesenchyme could be seen. Those beta 1(glo)/MC mice that survived into adulthood, however, had hyposalivation due to salivary gland fibrosis and acinar atrophy. Increased TGF-beta signaling was observed in the salivary gland with elevated phosphorylation of Smad2 and concomitant increase in ECM deposition. In particular, aberrant TGF-beta 1 overexpression caused salivary gland hypofunction in this mouse model because of the replacement of normal glandular parenchyma with interstitial fibrous tissue. These results further implicate TGF-beta in pathological cases of salivary gland inflammation and fibrosis that occur with chronic infections in the glands or with the autoimmune disease, Sjogren's syndrome, or with radiation therapy given to head-and-neck cancer patients. Laboratory Investigation (2010) 90, 543-555; doi: 10.1038/labinvest.2010.5; published online 8 February 2010
引用
收藏
页码：543 / 555
页数：13
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