Dynamic expression of IGFBP3 modulate dual actions of mineralization micro-environment during tooth development via Wnt/beta-catenin signaling pathway

by Selleckchem | Oct 31 2023

Background: Tooth development, as one of the major mineralized tissues in the body, require fine-tuning of mineralization micro-environment. The interaction between dental epithelium and mesenchyme plays a decisive role in this process. With epithelium-mesenchyme dissociation study, we found interesting expression pattern of insulin-like growth factor binding protein 3 (IGFBP3) in response to disruption of dental epithelium-mesenchyme interaction. Its action and related mechanisms as regulator of mineralization micro-environment during tooth development are investigated.

Results: Expressions of osteogenic markers at early stage of tooth development are significantly lower than those at later stage. BMP2 treatment further confirmed a high mineralization micro-environment is disruptive at early stage, but beneficial at later stage of tooth development. In contrast, IGFBP3's expression increased gradually from E14.5, peaked at P5, and decreased afterwards, demonstrating an inverse correlation with osteogenic markers. RNA-Seq and Co-immunoprecipitation showed that IGFBP3 regulates the Wnt/beta-catenin signaling pathway activity by enhancing DKK1 expression and direct protein-protein interaction. The suppression of the mineralization microenvironment effectuated by IGFBP3 could be reversed by the DKK1 inhibitor WAY-262611, further demonstrating that IGFBP3 exerted its influence via DKK1.

Conclusion: A deeper understanding of tooth development mechanisms is essential for tooth regeneration, which have great implications for dental care. The current study demonstrated that the IGFBP3 expression is regulated in accordance with the needs of the mineralization microenvironment during tooth development, and IGFBP3 exerts its modulating action on osteogenic/odontogenic differentiation of hDPSCs by DKK1-Wnt/ beta-catenin axis.

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Summary: This study focused on investigating the role of insulin-like growth factor binding protein 3 (IGFBP3) in tooth development and its regulation of the mineralization microenvironment. The researchers observed that the expression of osteogenic markers was lower at the early stage of tooth development but increased at later stages. Treatment with BMP2, a protein involved in bone development, disrupted the mineralization microenvironment at the early stage but was beneficial at later stages. In contrast, IGFBP3 expression gradually increased from E14.5, peaked at P5, and then decreased. This inverse correlation with osteogenic markers indicated that IGFBP3 plays a role in regulating the mineralization microenvironment during tooth development.

Further analysis using RNA-Seq and Co-immunoprecipitation revealed that IGFBP3 regulates the activity of the Wnt/beta-catenin signaling pathway. It does so by enhancing the expression of DKK1, a protein known to inhibit the Wnt pathway, and through direct protein-protein interaction. The researchers demonstrated that the suppression of the mineralization microenvironment caused by IGFBP3 could be reversed by the DKK1 inhibitor WAY-262611, indicating that IGFBP3 exerts its influence via DKK1.

The findings of this study contribute to a better understanding of tooth development mechanisms, which have significant implications for tooth regeneration and dental care. By elucidating the role of IGFBP3 in regulating the mineralization microenvironment and its interaction with the Wnt/beta-catenin signaling pathway, the study provides insights into potential strategies for promoting osteogenic/odontogenic differentiation, which is crucial for tooth regeneration efforts.