From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

Abstract

Among oral tissues, the periodontium is permanently subjected to mechanical forces resulting from chewing, mastication, or orthodontic appliances. Molecularly, these movements induce a series of subsequent signaling processes, which are embedded in the biological concept of cellular mechanotransduction (MT). Cell and tissue structures, ranging from the extracellular matrix (ECM) to the plasma membrane, the cytosol and the nucleus, are involved in MT. Dysregulation of the diverse, fine-tuned interaction of molecular players responsible for transmitting biophysical environmental information into the cell's inner milieu can lead to and promote serious diseases, such as periodontitis or oral squamous cell carcinoma (OSCC). Therefore, periodontal integrity and regeneration is highly dependent on the proper integration and regulation of mechanobiological signals in the context of cell behavior. Recent experimental findings have increased the understanding of classical cellular mechanosensing mechanisms by both integrating exogenic factors such as bacterial gingipain proteases and newly discovered cell-inherent functions of mechanoresponsive co-transcriptional regulators such as the Yes-associated protein 1 (YAP1) or the nuclear cytoskeleton. Regarding periodontal MT research, this review offers insights into the current trends and open aspects. Concerning oral regenerative medicine or weakening of periodontal tissue diseases, perspectives on future applications of mechanobiological principles are discussed.

Keywords: YAP/TAZ; extracellular matrix (ECM); gingipain proteases; mechanotransduction (MT); nuclear mechanotransduction (NMT); oral squamous cell carcinoma (OSCC); periodontitis; regeneration.

Figure 1

The role of focal adhesions and adherens junctions in mechanotransduction. (A): Focal adhesions (FAs) are adhesion structures that bind extracellular matrix (ECM) ligands via integrin receptors. The latter are composed of varying combinations of an α- and a β-subunit. Each heterodimer has specific ECM ligands (see Table 1). Intracellularly, integrins are linked to various signaling molecules that constitute a molecular clutch, which transmits mechanical information from the ECM into the cell’s interior and vice versa. Focal adhesion kinase (FAK), paxillin, talin, zyxin, vinculin, vasodilator-simulated phosphoprotein (VASP) and α-actinin are examples of important FAs proteins, connecting integrin receptors to the actin cytoskeleton (yellow). The small GTP-binding proteins Ras-related C3 botulinum toxin substrate 1 (Rac1), cell division control protein homologue 42 (Cdc42), and Ras homologue A (RhoA), together with Rho-associated, coiled-coil-containing protein kinase (ROCK) modulate the dynamic de- and repolymerization of globular (G)-actin (yellow dots) and filamentous (F)-actin. FAK activity and subcellular localization of yes-associated protein (YAP) and its cellular homologue transcriptional co-activator with PDZ motif (TAZ) are strongly interconnected. The linker of nucleoskeleton and cytoskeleton (LINC) complex couples the cytoplasmic cytoskeleton to the nucleus. Both mechanisms are important to regulate gene expression in response to mechanical signals. Details are described in the main text. (B): Cell-to-cell adhesion depends on adherens junctions (AJs). Cadherins, as exemplified by E-Cadherin, are transmembrane proteins that bind other cadherins on neighboring cells in a Ca²⁺-dependent manner (red dots). Intracellularly, cadherins are linked to various proteins, such as p120, α-catenin, β-catenin, and vinculin, which indirectly connect cadherins to the actin cytoskeleton (yellow). YAP/TAZ regulation is also dependent on AJs integrity. β-catenin can also serve as a transcription factor in the nucleus and its subcellular localization contributes to determining cell behavior. Further details are described in the main text.

Figure 2

The transcriptional co-activators YAP and TAZ are regulated by many cellular key players. Yes-associated protein (YAP) and its cellular homologue transcriptional co-activator with PDZ motif (TAZ) are master-regulators of cellular mechanotransduction. A plethora of upstream signals converge on these proteins. Nonetheless, there seems to be slight differences in the exact cellular functions of YAP and TAZ (details given in the main text). In the cytosol, YAP/TAZ are phosphorylated (P) and are bound by proteins from the 14-3-3 family, which prevent their translocation into the nucleus. YAP can additionally be bound by angiomotin (AMOT). Dephosphorylation of YAP/TAZ is mediated through regulators as diverse as focal adhesion kinase (FAK), cellular sarcoma (Src), coiled-coil-containing protein kinase 1 (ROCK), G-protein coupled receptors (GPCR), α-actinin, or the junctional proteins neurofibromatosis 2 (NF), KIBRA, and Salvador-homologue 1 (Sav1). RhoA also interacts with TAZ. In the nucleus, YAP may be trapped by zona occludens 2 (ZO-2) protein. Otherwise, YAP/TAZ interact with TEA domain family (TEAD) transcription factors to regulate gene expression. Genes written in green, such as cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), runt-related transcription factor 2 (RUNX2), osterix (OSX), osteopontin (OPN), ARMUS, collagen 1 (COL1), α-smooth muscle actin (α-SMA), cellular myelocytomatosis (c-myc), and cyclin D1 are upregulated by YAP/TAZ. Contrary to that, the pro-apoptotic B-cell lymphoma 2 (Bcl-2) as well as cyclin-dependent kinase inhibitor (CDKI) transcripts are downregulated by these transcriptional co-activators (yellow). Details are given in the main text.

Figure 3

LINC complex-dependent mechanotransduction at the cytosol–nucleus interface. Nuclear mechanotransduction is a process at the cytosol–nucleus interface, where mechanobiological information is exchanged between the cyctosol and the nucleus and vice versa. The linker of nucleoskeleton and cytoskeleton (LINC) complex consists of Nesprins, which are embedded in the outer nuclear membrane, and Sad1p and UNC-84 homology (SUN) proteins in the inner nuclear membrane. At the nuclear periphery and within the nucleus, LINC is connected to nuclear pore complexes (NPC), Emerin, and the nuclear intermediate filament system, which consists of Lamins. This is the reason why LINC is directly and/or indirectly connected to the chromatin and the nuclear actin filament system. In the cytoplasm, Nesprin interacts with all cytoskeletal systems. Microtubules interact with Nesprins through the motor proteins Kinesin (K) and Dynein (D); intermediate filaments are connected to Nesprins via Plectin. Filamentous actin (F-actin) can directly bind Nesprins. Mechanoresponsive translocation of YAP/TAZ through NPCs into the nucleus is also connected to nuclear mechanotransduction (NMT). Details are described in the main text.

Figure 4

P. gingivalis induces alveolar bone resorption through gingipain proteases. Secreted proteases, so-called gingipains (GPs), from the microbe Porphyromonas gingivalis (P. gingivalis) interact with the receptor activator of nuclear factor kappa-B ligand (RANK-L), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B (RANK) system of osteocytes and osteoclasts. In the presence of GPs, OPG is degraded, which favors RANK-L binding to RANK. Consequently, osteoclasts differentiate out of pre-osteoclasts through upregulation of Cathepsin K, matrix metalloproteinase 9 (MMP-9), and alkaline phosphatase type 5 (AP). Subsequently, osteoclasts can bind to the alveolar bone via αVβ3 integrins (green, dimeric sticks), which regulate actin cytoskeletal tension (yellow lines). Altogether, these processes favor alveolar bone resorption within resorption pits. Details are given in the main text.