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Li, C. Pathways Associated with Skeletal Sagittal Malocclusions. Encyclopedia. Available online: https://encyclopedia.pub/entry/16782 (accessed on 29 November 2023).
Li C. Pathways Associated with Skeletal Sagittal Malocclusions. Encyclopedia. Available at: https://encyclopedia.pub/entry/16782. Accessed November 29, 2023.
Li, Chenshuang. "Pathways Associated with Skeletal Sagittal Malocclusions" Encyclopedia, https://encyclopedia.pub/entry/16782 (accessed November 29, 2023).
Li, C.(2021, December 06). Pathways Associated with Skeletal Sagittal Malocclusions. In Encyclopedia. https://encyclopedia.pub/entry/16782
Li, Chenshuang. "Pathways Associated with Skeletal Sagittal Malocclusions." Encyclopedia. Web. 06 December, 2021.
Pathways Associated with Skeletal Sagittal Malocclusions
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This entry is adapted from the peer-reviewed paper 10.3390/ijms222313037

Skeletal class II and III malocclusions are craniofacial disorders that negatively impact people’s quality of life worldwide. Interestingly, several genes and enriched pathways are involved in both skeletal class II and III malocclusions, indicating the key regulatory effects of these genes and pathways in craniofacial development.

Pathways craniofacial disorders bone FGFR2

1. FGFR2 and Related Pathways

Fibroblast growth factor receptor 2 (FGFR2), a protein receptor for FGFs, affects osteoblasts’ proliferation, differentiation, and apoptosis, implicating it in bone growth [1]. Moreover, FGFR2 mutations have previously been linked to bone development and growth diseases, such as Apert syndrome [2], a genetic syndrome characterized by untimely early fusion of the skull bones during development that displays skeletal class III malocclusion [3][4]. Noticeably, Apert syndrome can arise from the S252W mutation in FGFR2 [4]. In this study, enrichment results showed that FGFR2 is involved in 19 of the top 20 skeletal class III malocclusion-associated pathways, echoing the assertion that this receptor and the associated FGFR pathway play a vital role in the sagittal disharmony of the maxillomandibular complex. Meanwhile, FGFR2 was also found to be linked to skeletal class II malocclusion and appeared in 17 of the top 20 skeletal class II malocclusion-associated pathways, suggesting that FGFR2’s influence is not limited to skeletal class III malocclusion but extends to skeletal class II malocclusion as well.
A variety of proteins have been identified as FGFR2 regulators in bone cells. For instance, fibroblast growth factor receptor substrate 2 (FRS2) displays a bi-directional modulation of FGFR2 function: via direct binding, FRS2 induces FGFR2 degradation [5][6], while also enhancing FGFR2-related activation of mitogen-activated protein kinase 1 (MAPK3/ERK 1) [5][6] and thus orchestrating FGFR2’s bioactivity in osteoblastogenesis [5][6][7]. In addition, FGFR2’s expression is also negatively regulated by non-specific alkaline phosphatase (TNAP) [8], which is encoded by ALPL [9]—a recognized skeletal class III malocclusion-associated gene[10]. Moreover, in osteoblasts, the translational product of the gene matrix metalloproteinase 14 (MMP14), termed MT-MMP, can prohibit the digestion of FGFR2 by ADAM metallopeptidase domain 9 (ADAM9) to preserve FGFR2’s function [11]. Interestingly, other members of the metalloproteinase family were also associated with skeletal malocclusions. For example, ADAMTS9 is a skeletal class II malocclusion-associated gene[12][13], while ADAMTS1, ADAMTSL1, and MMP13 [14][15][16] were associated with skeletal class III malocclusion. Thus, the crosstalk between the metalloproteinase family with FGFR2 may be interesting for further investigation in the context of skeletal malocclusion development and progression.
Regarding FGFR2’s downstream signal transduction, “Phospholipase C-mediated cascade; FGFR2” is one of the enriched pathways shared by skeletal class II and III malocclusions. In this pathway, phospholipase C-γ (PLCγ) is a substrate of FGFR and other receptors with tyrosine kinase activity [17]. Particularly, a previous study revealed that FGFR2 is responsible for PLCγ2 signaling activation in rat osteoblasts [18]. Furthermore, it is worth noting that PLCγ2 also promotes bone resorption by upregulating the expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor that plays a central role in promoting osteoclastogenesis [19]. Consequently, impairment of the PLCγ2 pathway depresses osteoclastogenesis [20]. In addition, NFATc1 is a skeletal class III malocclusion-associated gene. Thus, the FGFR2→PLCγ2→NFATc1 signal axis may be one of the essential bone growth and development regulating pathways that modulate osteoblast and osteoclast activities and thus contribute to skeletal malocclusion establishment. Meanwhile, since more FGFR2 SNPs were reported in skeletal class III malocclusion than in skeletal class II malocclusion, the influence of the FGFR2→PLCγ2→NFATc1 cassette may be more common and notable for skeletal class III malocclusion progression; however, further investigation targeting a population of greater diversity should be conducted to test this hypothesis.
Downregulated by FGFR2 [21], the “PI3K Cascade” is another skeletal class II and III malocclusion-associated pathway. Previous studies showed that inhibition of PI3K/p70 S6K cascades increases osteoblastic differentiation induced by bone morphogenetic protein 2 (BMP2) [22] while decreasing osteoclast activity [23]. These results suggest that the “PI3K Cascade” may govern bone growth and development concerning both osteoblasts and osteoclasts, while further research is needed to parse out how this pathway is associated with skeletal class II and class III malocclusions.
Interestingly, all reported FGFR2 SNPs are located in introns. As opposed to exons, which directly encode protein sequences, introns integrally regulate gene expression [24]. Some FGFR2 SNPs, such as rs10736303, rs1078806, and rs2981578, were only detected in skeletal class III malocclusion [25], suggesting that these SNPs may be responsible for mandibular prognathism and/or maxillary retrognathism. Surprisingly, two FGFR2 SNPs from the same intron, rs11200014 and rs2162540, are linked to both skeletal class II and III malocclusions [26][25]. It is difficult to explain the influence of these two FGFR2 SNPs if FGFR2 is considered as functioning in an isolated manner. One possible explanation is that after post-transcriptional modification, the respective introns are removed from the pre-mRNA and serve as miRNAs that regulate the expression of other skeletal malocclusion-associated genes, while the SNPs significantly alter their regulation targets and/or their effectiveness. Alternatively, these two intronic SNPs may make FGFR2 expression more sensitive to other influences and thus increase the risk of abnormal skeletal malocclusions. These additional influences may not be limited to other growth factors or cytokines involved in bone and cartilage growth and development. It is also possible that these two intronic FGFR2 SNPs indicate a scenario in which the affected bone is more vulnerable and sensitive to mechanical stimulations, such as those from the attached muscle tissue, as proposed by functional matrix theory [27][28].

2. Insulin Receptor Cascade

“Insulin receptor signaling cascade”, which was identified by pathway enrichment of the genes associated with skeletal class II and class III malocclusions, is known to promote osteoblast differentiation and osteocalcin (OCN) secretion [29][30][31]. Moreover, deletion of the Insulin-like growth factor 1 receptor (IGF1R) gene in mouse osteoblasts led to a striking decrease in cancellous bone volume, connectivity, and trabecular number, accompanied by an increase in trabecular spacing, while the rate of mineralization of osteoid was significantly decreased [32]. This correlation suggests that the “Insulin receptor signaling cascade” is essential for coupling matrix biosynthesis to sustained mineralization, which is particularly important during the pubertal growth spurt when rapid bone formation and consolidation are required [32].
Both insulin receptor substrate 1 (IRS1) and insulin receptor substrate 2 (IRS2) are involved in the signal transduction from IGF1R to its downstream mediator RAC-alpha serine/threonine-protein kinase (Akt1) [33]. Previous studies demonstrate that IRS1 in osteoblasts is indispensable for maintaining bone turnover [34]. In contrast, IRS2 is more predominantly required for bone formation over bone resorption [35]. Indeed, Akune et al. found that IRS2 signaling is not essential for osteoclastic cells’ differentiation, functioning, or survival [35]. Therefore, balanced IRS1/IRS2 signal transduction may contribute to the foundation of normal bone development and growth, while breaking the equilibrium of the “Insulin receptor signaling cascade” may trigger the formation of skeletal abnormalities, including skeletal class II and III malocclusions.
Because they are both connected to the PI3K→Akt axis, a complex interaction exists between FGF-related signal transduction and the “Insulin receptor signaling cascade” [21][33][36]. For example, not only is IRS1 involved in the “Insulin receptor signaling cascade” [33], but it is also a part of the “PI3K cascade” [37], and thus its influence may also extend to osteoclasts. In addition, stimulating the “Insulin receptor signaling cascade” could activate the parathyroid hormone (PTH) type 1 receptor (PTH1R) in osteoblasts/osteocytes to enhance the osteoblast-to-osteocyte transition [38]. Thus, the “Insulin receptor signaling cascade” may act as an intermediate coordinator of various signal pathways to integrate functions of theirs that are related to bone growth and development regulation and may warrant further investigation regarding its association with craniofacial sagittal discrepancy.

3. Runt-Related Transcription Factor 2 (RUNX2) and Notch Receptor 3 (NOTCH3)

As a well-known, predominant regulator of bone and cartilage growth and development [39][40], runt-related transcription factor 2 (RUNX2) promotes the activity of FGFR2 and FGFR3, leading to the proliferation of pre-osteoblastic cells [41]. Considering that RUNX2 promotes the differentiation of secondary chondrocytes and the formation of the cartilage of mandibular condyles [42], genetic variations that are more likely to have a negative influence on the RUNX2 gene may more frequently lead to mandibular retrognathism and thus induce skeletal class II malocclusion. This hypothesis is supported by previous animals studies that have shown that RUNX2-deficiency in mice resulted in a lack of mandibular condylar cartilage and mandibular bone [43]. In the current study, the RUNX2 gene was identified as the seed for three skeletal class II malocclusion-associated enriched pathways, as expected.
On the other hand, the NOTCH signaling pathway was associated with skeletal class III malocclusion in the current study, which is in agreement with previous research that demonstrates that a reduction in NOTCH3 signaling promoted osteogenic differentiation of mesenchymal stem stems located in a certain part of the mandible [44].
Together, the class-specific pathway identification of RUNX2 and NOTCH3 establishes confidence in the current skeletal malocclusion-associated enrichment.

4. Muscle-Related Genes with Skeletal Class II and III Malocclusions

4.1. Functional Matrix Theory

Excitingly, some skeletal class II and III malocclusion-associated genes identified in the current study have muscle-related functional annotations. One possible explanation for this is functional matrix theory, also called functional matrix hypothesis [27][28].
Functional matrix theory proposes that the growth and development of bone, including qualities such as attained length and width, are largely influenced by other body components [27][28]. For example, changes in the skeleton are not fully promoted by the genetic makeup of the bones but also rely on other biological components, particularly the skeletal muscles that belong to the periosteal category of the functional matrix [27]. Skeletal muscle activity could generate endogenous electrical fields that might orchestrate bone growth and development through various mechanisms [27]. On the other hand, the epigenetic event of muscle contraction may extend to bone cells’ genomes and thus modulate bone growth and development [45]. Therefore, as demonstrated in the current study, although genes that regulate skeletal muscle generation and activities may not be directly involved in bone and cartilage growth and development, a number of them nevertheless play a role in the growth and development of the maxilla and mandible, influencing characteristics such as length, and consequently are involved in the development of skeletal class II and III malocclusions. On the other hand, SNPs found in genes associated with bone and cartilage growth and development, either in introns or exons, may cause the gene isoform to be more sensitive to intracellular mechanotransduction and/or more vulnerable to muscle contraction-initiated epigenetic modification, and thus contribute to skeletal malocclusion determination.

4.2. Myosin Heavy Chain (MYH) Genes

Several MYH genes were previously associated with both types of malocclusions. In particular, higher expression levels of MYH3, MYH6, and MYH7 were detected in patients with mandibular retrognathism than in those with mandibular prognathism, while no significant difference was found between these two populations in regard to MYH1, MYH2, and MYH8 expression levels [46]. Thus, it is safe to say that the MYH proteins could be future research targets for craniofacial skeletal sagittal growth prediction and modification. At the same time, further investigations are warranted to determine whether, which of, and how the MYH molecules are involved in skeletal malocclusion establishment and if and what characters were overlooked in these previous investigations.

4.3. Other Muscle Function Genes

Histone deacetylase 4 (HDAC4) was found to be more highly expressed in the masseter muscle of patients with skeletal class III malocclusion than in patients with skeletal class II malocclusion [47]. In addition, two independent studies revealed higher expression of lysine acetyltransferase 6B (KAT6B) in the masseter muscle of skeletal class III malocclusion patients than in the same tissue type belonging to skeletal class II malocclusion patients, thereby indicating that KAT6B may be associated with mandibular prognathism [47][48]. Clearly, these genes could also be candidates for predicting patients’ expected development of skeletal malocclusion and their clinical correction prognoses in the future.
It is important to note that GWAS can only indicate the association between identified genes and a targeted clinical condition, while functional validation at the molecular level is a prerequisite for forming any conclusions. As stated above, current knowledge of the functions of the skeletal class II and III-associated genes in the musculoskeletal system is extensive. However, the specific impacts of these genes on the craniofacial region are largely unknown. We hope that the current review and the conducted pathway enrichment can provide clues about the potential relationships among the identified genes and identify which genes and pathways can be prioritized for functional validation in future studies. We would also like to emphasize that the current review focused on the sagittal dimension, which is a crucial dimension in orthodontic diagnosis and treatment planning. Because craniofacial structure develops three-dimensionally, further evaluation of the genes involved in the vertical and transverse growth and development of the craniofacial structure is also needed.

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