The Role of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Enamel Formation.

Abstract

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF), an autosomal recessive multiorgan disorder. In addition to respiratory, digestive, and reproductive pathologies, patients with CF also exhibit higher rates of enamel defects. CFTR is an anion channel expressed in maturation-stage ameloblasts and is known for its role in chloride and bicarbonate conductance, a function thought to promote enamel mineralization through the neutralization of protons released during hydroxyapatite formation. Previous studies of CFTR global knockout mice have shown hypomineralization and acidification of the maturation-stage enamel matrix. However, the systemic nature of CF and the contribution of extrinsic factors may contribute to these findings. To determine how CFTR specifically contributes to amelogenesis, we generated a conditional knockout mouse in which CFTR loss-of-function is driven by Cre expression under the promoter of the maturation-stage ameloblast marker, Odam. CFTR loss-of-function resulted in the formation of hypomineralized enamel. The enamel matrix was acidified, and loss of matrix pH cycling coincided with arrested ameloblast modulation as indicated by failed re-localization of tight/ gap junctions and ion transporters to the ameloblast distal membrane. Amelogenin hydrolysis was reduced and retained in the maturing enamel matrix, which was associated with reduced Klk4 expression and activity. Transcriptional analyses of incisor ameloblasts showed reduced expression of acid-base regulators, consistent with dysregulation of both intracellular and extracellular pH. Together, these findings show multiple functions of CFTR in incisor enamel maturation, including regulation of intra/ extracellular pH, ameloblast modulation, and extracellular matrix remodeling.