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Journal ArticleDOI

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

31 May 2021-Vol. 11, Iss: 6, pp 824
TL;DR: In this paper, a review of periodontal mechanotransduction research is presented, which offers insights into the current trends and open aspects, and perspectives on future applications of mechanobiological principles are discussed.
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.
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Journal ArticleDOI
TL;DR: In this paper, a systematic review was conducted to identify all related in vitro studies reporting tension application on periodontal ligament fibroblasts and summarize their findings regarding force parameters, including magnitude, frequency and duration.
Abstract: Orthodontic tooth movement is based on the remodeling of tooth-surrounding tissues in response to mechanical stimuli. During this process, human periodontal ligament fibroblasts (hPDLFs) play a central role in mechanosensing and mechanotransduction. Various in vitro models have been introduced to investigate the effect of tension on hPDLFs. They provide a valuable body of knowledge on how tension influences relevant genes, proteins, and metabolites. However, no systematic review summarizing these findings has been conducted so far. Aim of this systematic review was to identify all related in vitro studies reporting tension application on PDLFs and summarize their findings regarding force parameters, including magnitude, frequency and duration. Genes, proteins, and metabolites expression data was extracted and summarized. Studies’ risk of bias was assessed using tailored risk of bias tools. Signaling pathways were identified by protein-protein interaction (PPI) networks using STRING and GeneAnalytics. According to our results, Flexcell Strain Unit® and other silicone-plate or elastic membrane-based apparatuses were mainly adopted. Frequencies of 0.1Hz and 0.5Hz were predominantly applied for dynamic equibiaxial and uniaxial tension, respectively. Magnitudes of 10% and 12% were mostly employed for dynamic tension while 2.5% for static tension. The 10 most commonly investigated genes, proteins and metabolites were identified, mainly involved in osteogenesis, osteoclastogenesis or inflammation. Gene-set enrichment analysis and PPI networks gave deeper insight into the involved signaling pathways. This review represents a brief summary of the massive body of knowledge in this field, and will also provide suggestions for future researches on this topic.

10 citations

Journal ArticleDOI
TL;DR: These novel in situ-cross-linked electrospun nonwoven scaffolds allow for efficient adhesion and survival of hMSCs and PDLFs, which rendered this platform an interesting candidate for periodontal tissue engineering.
Abstract: Periodontal diseases affect millions of people worldwide and can result in tooth loss. Regenerative treatment options for clinical use are thus needed. We aimed at developing new nonwoven-based scaffolds for periodontal tissue engineering. Nonwovens of 16% gelatin/5% hydroxyapatite were produced by electrospinning and in situ glyoxal cross-linking. In a subset of scaffolds, additional porosity was incorporated via extractable polyethylene glycol fibers. Cell colonization and penetration by human mesenchymal stem cells (hMSCs), periodontal ligament fibroblasts (PDLFs), or cocultures of both were visualized by scanning electron microscopy and 4′,6-diamidin-2-phenylindole (DAPI) staining. Metabolic activity was assessed via Alamar Blue® staining. Cell type and differentiation were analyzed by immunocytochemical staining of Oct4, osteopontin, and periostin. The electrospun nonwovens were efficiently populated by both hMSCs and PDLFs, while scaffolds with additional porosity harbored significantly more cells. The metabolic activity was higher for cocultures of hMSCs and PDLFs, or for PDLF-seeded scaffolds. Periostin and osteopontin expression was more pronounced in cocultures of hMSCs and PDLFs, whereas Oct4 staining was limited to hMSCs. These novel in situ-cross-linked electrospun nonwoven scaffolds allow for efficient adhesion and survival of hMSCs and PDLFs. Coordinated expression of differentiation markers was observed, which rendered this platform an interesting candidate for periodontal tissue engineering.

5 citations

Journal ArticleDOI
TL;DR: The ultimate goal of periodontal therapy is homeostatic regeneration of lost attachment of alveolar bone and gingival connective tissue to the exposed root surfaces.

3 citations

Journal ArticleDOI
TL;DR: The ultimate goal of periodontal therapy is homeostatic regeneration of lost attachment of alveolar bone and gingival connective tissue to the exposed root surfaces as discussed by the authors .

2 citations

Journal ArticleDOI
TL;DR: In this paper, the role of FAK in epithelial morphogenesis was investigated by quantifying cell layers and detecting the expression of biomarkers of epithelial differentiation and homeostasis.
Abstract: By employing an innovative biohybrid membrane, the present study aimed at elucidating the mechanistic role of the focal adhesion kinase (FAK) in epithelial morphogenesis in vitro over 4, 7, and 10 days. The consequences of siRNA-mediated FAK knockdown on epithelial morphogenesis were monitored by quantifying cell layers and detecting the expression of biomarkers of epithelial differentiation and homeostasis. Histologic examination of FAK-depleted samples showed a significant increase in cell layers resembling epithelial hyperplasia. Semiquantitative fluorescence imaging (SQFI) revealed tissue homeostatic disturbances by significantly increased involucrin expression over time, persistence of yes-associated protein (YAP) and an increase of keratin (K) 1 at day 4. The dysbalanced involucrin pattern was underscored by ROCK-IISer1366 activity at day 7 and 10. SQFI data were confirmed by quantitative PCR and Western blot analysis, thereby corroborating the FAK shutdown-related expression changes. The artificial FAK shutdown was also associated with a significantly higher expression of filaggrin at day 10, sustained keratinocyte proliferation, and the dysregulated expression of K19 and vimentin. These siRNA-induced consequences indicate the mechanistic role of FAK in epithelial morphogenesis by simultaneously considering prospective biomaterial-based epithelial regenerative approaches.

2 citations

References
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Journal ArticleDOI
15 Jan 1999-Science
TL;DR: Biochemical signaling networks were constructed with experimentally obtained constants and analyzed by computational methods to understand their role in complex biological processes and raise the possibility that information for "learned behavior" of biological systems may be stored within intracellular biochemical reactions that comprise signaling pathways.
Abstract: Many distinct signaling pathways allow the cell to receive, process, and respond to information. Often, components of different pathways interact, resulting in signaling networks. Biochemical signaling networks were constructed with experimentally obtained constants and analyzed by computational methods to understand their role in complex biological processes. These networks exhibit emergent properties such as integration of signals across multiple time scales, generation of distinct outputs depending on input strength and duration, and self-sustaining feedback loops. Feedback can result in bistable behavior with discrete steady-state activities, well-defined input thresholds for transition between states and prolonged signal output, and signal modulation in response to transient stimuli. These properties of signaling networks raise the possibility that information for "learned behavior" of biological systems may be stored within intracellular biochemical reactions that comprise signaling pathways.

1,679 citations

Journal ArticleDOI
30 Aug 2013-Science
TL;DR: In this article, proteomics analyses revealed that levels of the nucleoskeletal protein lamin-A scaled with tissue elasticity, as did levels of collagens in the extracellular matrix that determine E.
Abstract: Tissues can be soft like fat, which bears little stress, or stiff like bone, which sustains high stress, but whether there is a systematic relationship between tissue mechanics and differentiation is unknown. Here, proteomics analyses revealed that levels of the nucleoskeletal protein lamin-A scaled with tissue elasticity, E, as did levels of collagens in the extracellular matrix that determine E. Stem cell differentiation into fat on soft matrix was enhanced by low lamin-A levels, whereas differentiation into bone on stiff matrix was enhanced by high lamin-A levels. Matrix stiffness directly influenced lamin-A protein levels, and, although lamin-A transcription was regulated by the vitamin A/retinoic acid (RA) pathway with broad roles in development, nuclear entry of RA receptors was modulated by lamin-A protein. Tissue stiffness and stress thus increase lamin-A levels, which stabilize the nucleus while also contributing to lineage determination.

1,563 citations

Journal ArticleDOI
TL;DR: Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.
Abstract: Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix (ECM) that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function. Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.

1,449 citations

Journal ArticleDOI
TL;DR: YAP/TAZ appear at the centerpiece of a signaling nexus by which cells take control of their behavior according to their own shape, spatial location and growth factor context, and are appealing therapeutic targets in cancer and regenerative medicine.
Abstract: The transcriptional regulators YAP and TAZ are the focus of intense interest given their remarkable biological properties in development, tissue homeostasis and cancer. YAP and TAZ activity is key ...

1,250 citations

Journal ArticleDOI
TL;DR: It is shown that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation.
Abstract: The Hippo tumor suppressor pathway restricts organ size in Drosophila and mammals by antagonizing the oncoprotein Yki/YAP (Zeng and Hong 2008; Pan 2010; Zhao et al. 2010; Halder and Johnson 2011). Central to the Hippo pathway is a kinase cascade leading from the protein kinase Hpo/Mst to Yki/YAP. The Hippo kinase cascade, in turn, is regulated by a complex network of proteins, which most notably includes the Neurofibromin 2 (NF2)/Merlin tumor suppressor. Consistent with the critical role of Hippo signaling in normal tissue homeostasis, the YAP oncoprotein is overexpressed or hyperactivated in a wide spectrum of human cancers due to YAP locus amplification or genetic/epigenetic inactivation of upstream tumor suppressors. Small molecule inhibitors of YAP will not only provide important tools for pharmacological manipulation of Hippo signaling, but also bear tremendous potential for developing therapeutic drugs against human cancers caused by defective Hippo signaling. As a transcriptional coactivator, YAP has been reported to bind to several DNA-binding transcription factors (for review, see Pan 2010). Among the reported YAP partners, the TEAD/TEF transcription factors are best characterized (Vassilev et al. 2001; Chen et al. 2010; Li et al. 2010). Genetic studies in Drosophila revealed an interesting property of its single TEAD ortholog, Scalloped (Sd): While Sd is required for tissue overgrowth driven by hyperactivated Yki, Sd (but not Yki) is largely dispensable for normal tissue growth (Huang et al. 2005; Wu et al. 2008). Thus, Sd/TEAD may belong to a growing list of genes that contribute to “non-oncogene addiction”—genes that are not mutated in cancers but are critically required for cancer growth (Luo et al. 2009). The dispensability of Sd for normal growth in Drosophila suggests that the mammalian TEAD factors may be ideal targets for selective inhibition of oncogenic growth driven by YAP hyperactivation with minimal effects on normal tissue homeostasis. Although previous studies have shown that the TEAD factors are required for YAP's oncogenic activity in cell cultures (Zhao et al. 2008), whether the TEAD factors (or any of the other reported YAP partners) are required for YAP-mediated tumorigenesis has not been determined in intact mammalian tissues. It also remains to be seen whether inhibition of the mammalian TEAD factors, like loss of Drosophila Sd, has minimal impact on normal tissue homeostasis and physiology. Such information will shed light on the “therapeutic window” of pharmacological strategies aimed at disrupting the TEAD–YAP complex as a selective means against YAP-driven tumorigenesis. Using a combination of genetic suppression in transgenic mice and discovery of lead compounds with in vitro and in vivo activities, we provide here proof of principle that inhibiting TEAD–YAP interactions is a promising and pharmacologically viable strategy against the YAP oncoprotein.

1,149 citations