Bone morphogenetic protein (BMP) is a member of the transforming growth factor-β (TGF-β) superfamily, which is involved in the development of almost all tissues, such as bone, cartilage, muscle, kidney, blood vessels, etc. BMP and its mediated signaling pathways play a very important role in root development. Root development is a process of epithelial and mesenchymal interaction, and BMP and its receptors are expressed in both epithelial cells and mesenchymal cells of the tooth germ. BMP signaling plays a very active role in the formation of epithelial root sheaths and the differentiation of dentin-forming cells in the root.
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BMP Ligand
According to the amino acid homology sequence, structure, and function, BMP can be divided into 4 subcategories: 1) BMP-2 and BMP-4 are a subclass, which has up to 80% homology sequence, differing in that the amino acid terminus of BMP-2 has a heparin-binding domain. 2) BMP-3 and BMP-3B (GDF-10) are classified into one subcategory. 3) BMP-5, BMP-6, BMP-7 (OP-1), BMP-8a and BMP-8b are a subcategory. 4) BMP-12, BMP-13 and BMP-14 are a unique subclass. Mature BMP monomers contain seven cysteines, six of which form intramolecular disulfide bonds, and the rest dimerize with another BMP monomer via covalent disulfide bonds to form active homo- or heterodimers.
BMP Receptor
BMP receptors consist of three parts: an extracellular binding region, a transmembrane region, and an intracellular serine/threonine kinase activation region. Based on differences in the intracellular region, BMP receptors are classified into Type I receptors and Type II receptors. Type I BMP receptors include BMPR1A (BMP receptor type 1A, also known as activin receptor-like kinases 3, ALK3), ACVR1 (activin A receptor type 1, also known as ALK2), and BMPR1B (BMP receptor type 1B, also known as ALK6). Type II BMP receptors include BMPR-II (BMP receptor type II), ACVR-II A (activin A receptor type II), and ACVR-II B (activin B type II receptor). Among Type II receptors, BMPR-II serves exclusively as a BMP receptor, while the other two receptors are shared among BMPs, activins, and myostatin.
BMP Signaling Pathway
BMP forms a heteromeric tetramer with Type I and Type II receptors, activating the Type II receptor. The Type II receptor phosphorylates the glycine/serine-rich region of the Type I receptor, initiating both the canonical BMP signaling pathway, dependent on Smad proteins, and the non-canonical BMP signaling pathway, which is Smad-independent. In contrast to the TGF-β signaling pathway, BMP can bind to the Type I receptor even in the absence of the Type II receptor. However, the affinity of this binding decreases significantly when both Type I and Type II receptors are present. Smad proteins, present in the cell, transduce signals from the cell surface to the nucleus by binding BMP and receptors. There are three classes of Smad proteins: receptor-regulated Smad (R-Smad), including Smad1, Smad5, and Smad9; common Smad (co-Smad), namely Smad4; and inhibitory Smad (I-Smad), including Smad6 and Smad7. Activated R-Smad, phosphorylated by the Type I BMP receptor, forms a complex with Smad4, translocating into the cell nucleus to activate the transcription of target genes. One complex consists of two R-Smads and one Smad4. Studies have found that Smad9 not only transduces BMP signals to the nucleus but also forms a complex with Smad1, entering the nucleus to bind with DNA, inhibiting the transcription of target genes. In addition, regulatory factors play a crucial role in BMP signaling transduction, such as the cytoplasmic ubiquitin ligases Smurf1/2, which can be recruited by Smad6/7 to ubiquitinate R-Smads, promoting their degradation and thus inhibiting BMP signaling transduction.
Fig. 1 The BMP signaling pathway in apical papilla cells during tooth root development. (Hosoya A., et al., 2008).
BMP can also activate non-canonical BMP signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway, including extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and phosphoinositol-3 kinase (PI3K).
BMP regulates different cellular responses through both canonical and non-canonical pathways, participating in almost every process from differentiation to maturation in osteoblasts. The specific knockout of Smad1 in osteoblasts partially inhibits the BMP signaling pathway, resulting in suppressed proliferation and differentiation of osteoblasts, leading to an osteoporotic phenotype in mice. The specific knockout of Tak-1 (TGF-β activated kinase 1) in chondrocytes and mesenchymal cells inhibits the downstream MAPK pathway, disrupting the growth plate structure and impairing terminal differentiation of chondrocytes.
The Role of BMP Signaling Pathway in Tooth Root Development
The BMP signaling pathway plays a crucial role in tooth root development, influencing both HERS (Hertwig's Epithelial Root Sheath) and dental pulp mesenchyme. In HERS, BMP signaling, specifically the BMP-Smad4-Shh-Gli1-Sox2 cascade, regulates root development. Loss of BMP signaling in HERS, disrupts the epithelial stem cell microenvironment, preventing normal extension of HERS and resulting in impaired root formation. Additionally, the downstream target gene Msx2, a transcription factor in the BMP pathway, affects HERS formation, as observed in Msx2-/- mice with delayed root development. Overexpression of BMP signaling inhibitor Noggin in epithelial cells leads to tooth loss, shortened roots, and decreased proliferation activity in HERS and dental pulp mesenchyme.
In dental pulp mesenchyme, BMP signaling is essential for the differentiation of dental pulp cells. Genetic knockout of bmp2 in mesenchymal progenitor cells disrupts the formation of polarized dental pulp cells, resulting in short roots and thin dental pulp. Interactions with other signaling pathways, such as Wnt, further highlight the complexity of BMP signaling in tooth root development. Notably, BMP signaling deficiencies can lead to abnormalities resembling human conditions like taurodontism and congenital short roots. Understanding the interplay between BMP signaling and tooth root diseases in humans is crucial for developing effective clinical treatments.
References
- Wang R. N.; et al. Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes & Diseases. 2014, 1(1): 87-105.
- Hosoya A.; et al. BMP4 signaling regulates formation of Hertwig's epithelial root sheath during tooth root development. Cell and Tissue Research. 2008, 333: 503-509.
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