Notum as a Crucial Regulator of Matrix Integrity in Dentinogenesis

Dentinogenesis, the formation of dentin, requires precise coordination of cellular differentiation, extracellular matrix synthesis, and signaling regulation. Here, we elucidate the role of Notum, a secreted Wnt inhibitor, in orchestrating these processes during dentin formation. In Notum^−/− mice, dentin exhibited a thicker yet dysplastic structure with disrupted tubule organization and impaired mineralization, deviating from the functional architecture of healthy dentin. Loss of Notum led to excessive activation of Wnt/β-catenin signaling within the dentin-pulp complex and enhanced expression of odontogenic genes, including dentin sialophosphoprotein (Dspp), and dentin matrix protein 1 (Dmp1). However, this upregulation was uncoupled from proper extracellular matrix composition and mineralization, indicating that initial odontoblast differentiation alone is insufficient for functional dentin formation. At the molecular level, Notum deficiency disrupted matrix integrity, characterized by reduced collagen organization and increased expression of non-collagenous matrix proteins such as bone sialoprotein (Bsp). Collectively, these findings highlight Notum as a critical modulator that fine-tunes Wnt/β-catenin signaling to coordinate cellular differentiation with matrix organization during dentinogenesis. Therapeutic targeting Notum may offer new strategies for restoring dentin integrity and enhancing regenerative outcomes.