The interaction between Hertwig's epithelial root sheath (HERS) and surrounding mesenchymal cells is crucial for root dentin formation. HERS influences tooth root development and odontoblast differentiation; however, further research is needed to elucidate its regulatory mechanisms.

A new study published in the Genes & Diseases journal by researchers from the Affiliated Hospital of Stomatology of Chongqing Medical University, the Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Southwest University, and the University of Chicago Medical Center provides mechanistic insights into how Bmp9 signaling impacts tooth root development.

The authors have previously shown that Bmp9 is crucial for tooth and alveolar bone formation, and in this study report that Bmp9 signaling modulates tooth root development by regulating the development of odontoblasts and HERS.

The authors generated Bmp9-KO mice and, upon comparison with their wild-type (WT) mice, observed that BMP9 plays a critical role in molar root development, dentin mineralization, and root elongation during early odontogenesis. Knockdown of Bmp9 inhibited odontoblast differentiation and also impacted the normal development of the mandibular first molars, as evidenced by shorter molar roots, wider apical foramen, and reduced dentin thickness. Bmp9 ablation disrupted odontoblast polarization, affecting their secretory capacity and weakening DSPP secretion, resulting in delayed dentin mineralization, increased collagen type I deposition, and reduced root length.

Furthermore, knockdown of Bmp9 inhibited cell proliferation within the HERS, thereby affecting HERS elongation and bending, and formation of the root apical foramen, which resulted in shorter roots, thinner dentin, and an unclosed apical foramen in Bmp9-KO mandibular first molars. Additional experiments involving Bmp9 overexpression and knockdown in primary HERS cells showed that “Bmp9 signaling modulates both HERS cell proliferation and intercellular junctions, thereby contributing to the proper development of tooth roots.”

Comparative transcriptomic profiling and pathway analysis (GO and KEGG) revealed that Bmp9 maintains HERS cell proliferation, junction homeostasis, and drives root morphogenesis by integrating a multidimensional regulatory network involving TGF-β and Wnt signaling and cell-cell connections.

In conclusion, this study is the first to report that BMP9 signaling influences root odontoblast function by regulating cell proliferation and intercellular junctions within HERS, thereby affecting the overall developmental trajectory of molar roots. The authors highlight the need for further research to identify specific binding sites and the mechanism of action of Bmp9 in regulating HERS proliferation and intercellular connectivity integrity.

Reference

Title of the original paper: Bmp9 modulates cell proliferation and intercellular junctions in HERS during tooth root development

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch

DOI: https://doi.org/10.1016/j.gendis.2025.101777

Funding Information:

• National Natural Science Foundation of China (No. 82470977; No. 32070539)
• Natural Science Foundation of Chongqing, China (No. 2024ZYYB005)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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