In our previous study, we reported two osteopetrosis patients with CLCN7 mutations, who had impacted teeth, enamel dysplasia, malformed teeth, altered tooth eruption and root dysplasia. Human CLCN7 encoding voltage-gated chloride channel 7 (ClC-7) is one of the key molecules involved in osteopetrosis. Currently, the candidate genes of osteopetrosis include IKBKG, CLCN7, OSTM1, TCIRG1, PLEKHM1, CAII, RANK, and RANKL. Osteopetrosis is a group of genetic disorders characterized by increased bone mass and density due to defective bone resorption. Keywords: osteopetrosis, ClC-7, craniofacial bone, tooth, SB431542 Introduction The mechanism chain of ClC-7/CTSK/ TGF-β/BMP/SMAD might explain the typical craniofacial bone and tooth changes in osteopetrosis as well as pycnodysostosis patients. The ClC-7 involved CTSK/BMP and SMAD changes were also confirmed in mouse bone marrow stromal cells.Ĭonclusion: These findings highlighted the vital role of clcn7 in zebrafish craniofacial bone and tooth development and mineralization, revealing novel insights for the causation of osteopetrosis with CLCN7 mutations. SB431542 inhibitor of TGF-β pathway partially rescued the aforementioned craniofacial bone and tooth defects of clcn7 morphants. ClC-7/CTSK further altered the balance of TGF-β/BMP signaling pathway, causing elevated TGF-β-like Smad2 signals and reduced BMP-like Smad1/5/8 signals in clcn7 morphants. The craniofacial phenotype severity also presented a dose-dependent relationship with the levels of ClC-7 and CTSK. Loss of clcn7 function resulted in lysosomal storage in the brain and jaw as well as downregulated cathepsin K (CTSK). clcn7 knockdown in zebrafish reproduced the craniofacial cartilage defects and various dental malformations combined the decreased levels of col10a1, sp7, dlx2b, eve1, and cx43. Our four pedigrees with CLCN7 mutations confirmed the aforementioned clinical features. Results: Over 84% of osteopetrosis patients in the literature had some typical craniofacial and tooth phenotypes, including macrocephaly, frontal bossing, and changes in shape and proportions of facial skeleton, and these unique features are more severe and frequent in autosomal recessive osteopetrosis than in autosomal dominant osteopetrosis patients. Fourth, mouse marrow stromal cells were further primarily cultured to detect ClC-7 related mRNA and protein changes using siRNA, Q-PCR and western blotting. General observation, whole mount alcian blue and alizarin red staining, whole mount in situ hybridization, scanning electron microscope observation, lysoSensor staining, Q-PCR and western blotting were performed to observe the in vivo characteristics of craniofacial bone and tooth changes. Third, we used a zebrafish model with clcn7 morpholino treatment to detect the effects of ClC-7 deficiency on the development of craniofacial and dental phenotypes. Second, four osteopetrosis pedigrees with CLCN7 mutations were recruited from our clinic for gene testing and clinical analysis of their craniofacial and dental phenotypes. Methods: First, we collected 80 osteopetrosis cases from the literature and compared their craniofacial and dental phenotypes. It is unclear whether these phenotypes are the typical features of CLCN7 involved osteopetrosis and whether ClC-7 could regulate the development of craniofacial bone and tooth in some signaling pathways. In our previous clinical practice, we noticed that osteopetrosis patients with CLCN7 mutations had some special deformities in craniofacial morphology and tooth dysplasia. Human CLCN7 encodes voltage-gated chloride channel 7 (ClC-7) mutations of CLCN7 lead to osteopetrosis which is characterized by increased bone mass and impaired osteoclast function. Select the file that you have just downloaded and select import option Reference Manager (RIS). ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth. Zhang Y, Ji D, Li L, Yang S, Zhang H, Duan X.
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