SCPPPQ1 Regulates Enamel Mineralization via the TGF-β1/Smad3 Signaling Pathway

Secretory Calcium-Binding Phosphoprotein Proline-Glutamine Rich 1 (SCPPPQ1) has emerged as a critical contributor to tooth development; however, its precise molecular role in enamel formation remains largely uncharacterized. To investigate its functional significance, we employed both an in vivo SCPPPQ1 knockout (KO) mouse model and an in vitro ameloblast-like cell (ALC) line stably overexpressing SCPPPQ1. Histological and micro-computed tomography analyses revealed that SCPPPQ1 deficiency resulted in pronounced enamel mineralization defects. Conversely, SCPPPQ1 overexpression significantly enhanced mineral deposition in ALCs and induced the upregulation of key osteogenic and amelogenic markers, including Runx2 and Alp. Mechanistically, the pro-mineralization effects of SCPPPQ1 were abolished by SIS3, a selective inhibitor of Smad3 phosphorylation, indicating that SCPPPQ1 exerts its effects through activation of the TGF-β1/Smad3 signaling pathway. Collectively, our findings identify SCPPPQ1 as a pivotal positive regulator of amelogenesis that promotes enamel mineralization via the TGF-β1/Smad3 axis. These results not only advance our understanding of the molecular mechanisms underlying enamel formation but also highlight SCPPPQ1 as a promising therapeutic target for enamel repair.