ClC-7 Deficiency Impairs Tooth Development and Eruption.

He Wang,Buling Wu,Yanli Zhang,Rong Zhang,Jin Liu,Yutao Zhang,Shan Gao,Huiming He,Zhe Wang,Xiaohong Duan,Jinwen Ni,Meng Pan

doi:10.1038/srep19971

Abstract

CLCN7 gene encodes the voltage gated chloride channel 7 (ClC-7) in humans. The mutations in CLCN7 have been associated with osteopetrosis in connection to the abnormal osteoclasts functions. Previously, we found that some osteopetrosis patients with CLCN7 mutations suffered from impacted teeth and root dysplasia. Here we set up two in vivo models under a normal or an osteoclast-poor environment to investigate how ClC-7 affects tooth development and tooth eruption. Firstly, chitosan-Clcn7-siRNA nanoparticles were injected around the first maxillary molar germ of newborn mice and caused the delay of tooth eruption and deformed tooth with root dysplasia. Secondly, E13.5 molar germs infected with Clcn7 shRNA lentivirus were transplanted under the kidney capsule and presented the abnormal changes in dentin structure, periodontal tissue and cementum. All these teeth changes have been reported in the patients with CLCN7 mutation. In vitro studies of ameloblasts, odontoblasts and dental follicle cells (DFCs) were conducted to explore the involved mechanism. We found that Clcn7 deficiency affect the differentiation of these cells, as well as the interaction between DFCs and osteoclasts through RANKL/OPG pathway. We conclude that ClC-7 may affect tooth development by directly targeting tooth cells, and regulate tooth eruption through DFC mediated osteoclast pathway.

Highlights

chloride channel 7 (ClC-7) is encoded by CLCN7 in humans and the mutations in the CLCN7 gene cause two different types of osteopetrosis: autosomal dominant osteopetrosis type II (OMIM166600) and autosomal recessive osteopetrosis type IV (OMIM611490)[1]
The osteopetrosis patients caused by osteoclasts dysfunction usually presented impacted and malformed teeth and the involved genes include RANKL15,16, TCIRG117, etc
ClC-7 is highly expressed in the ruffled membrane of osteoclasts, and responsible for acidifying resorption lacuna

Summary

Introduction

ClC-7 is encoded by CLCN7 in humans and the mutations in the CLCN7 gene cause two different types of osteopetrosis: autosomal dominant osteopetrosis type II (OMIM166600) and autosomal recessive osteopetrosis type IV (OMIM611490)[1]. Besides the identical bone phenotypes of osteopetrosis, the patients presented hypodontia, enamel dysplasia, malformed teeth, altered tooth eruption, and impacted teeth[2]. The tooth germs were able to form but did not erupt in Clcn7−/− mice[3]. A spontaneous autosomal recessive osteopetrosis mouse model with the mutant allele in Clcn[7] locus displayed no tooth eruption or tooth root formation[4]. It is possible that the dysplastic tooth and the impact of tooth germ in osteopetrosis patients or in Clcn7−/− mice are caused by the dysfunctional osteoclasts. The locations of ClC-7 in ameloblast, odontoblast, dental papilla cells and dental follicle cells (DFCs)[13,14] raise one hypothesis, whether ClC-7 directly affect tooth development. We investigated the role of ClC-7 roles in the differentiation and biological functions of several tooth cells, such as ameloblasts, odontoblasts and DFCs

Methods

Results

Conclusion