Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression.

Xiaohua Xie,Yongbo Lu,Chao Liu,Xiaofang Wang,Priyam H Jani,Chunlin Qin,Hua Zhang,Bin Zhang

doi:10.1038/srep25364

Abstract

Amelogenesis Imperfecta (AI) can be caused by the deficiencies of enamel matrix proteins, molecules responsible for the transportation and secretion of enamel matrix components, and proteases processing enamel matrix proteins. In the present study, we discovered the double deletion of bone morphogenetic protein 2 (Bmp2) and bone morphogenetic protein 4 (Bmp4) in the dental epithelium by K14-cre resulted in hypoplastic enamel and reduced density in X-ray radiography as well as shortened enamel rods under scanning electron microscopy. Such enamel phenotype was consistent with the diagnosis of hypoplastic amelogenesis imperfecta. Histological and molecular analyses revealed that the removal of matrix proteins in the mutant enamel was drastically delayed, which was coincided with the greatly reduced expression of matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4). Although the expression of multiple enamel matrix proteins was down-regulated in the mutant ameloblasts, the cleavage of ameloblastin was drastically impaired. Therefore, we attributed the AI primarily to the reduction of MMP20 and KLK4. Further investigation found that BMP/Smad4 signaling pathway was down-regulated in the K14-cre;Bmp2f/f;Bmp4f/fameloblasts, suggesting that the reduced MMP20 and KLK4 expression may be due to the attenuated epithelial BMP/Smad4 signaling.

Highlights

Tooth enamel, the hardest tissue in the human body, contains inorganic and organic components
These results indicated that the double deletion of Bmp[2] and Bmp[4] from the dental epithelium caused amelogenesis imperfecta (AI) in these mice
The remarkable enamel defects observed in the double bone morphogenetic protein 2 (Bmp2)- and bone morphogenetic protein 4 (Bmp4)-knockout mice indicated the indispensable role of these two growth factors in amelogenesis

Summary

Introduction

The hardest tissue in the human body, contains inorganic and organic components. Further analyses demonstrated that the cleavage of AMEL was impaired in the MMP20 deficient mice[11], and hypomature AI in the KLK4 knock-out /LacZ knock-in mice was characterized by significantly retained ENAM in the mature enamel matrix[15]. All these results demonstrate that the processing of enamel matrix proteins by MMP20 and KLK4 is essential for the normal process of amelogenesis. We ablated Bmp[2] and Bmp[4] from mouse epithelium by breeding the Bmp2- and Bmp4-floxed mice with K14-cre mice and analyzed the enamel in the double Bmp2- and Bmp4-knockout mice

Methods

Results

Conclusion