Regulatory Mechanism of ERKs Pathway on Orthodontic Force Signal Transduction and Osteogenic Differentiation

Ziliang Yang1,2, Sihui Hu3, Xinyi Li4

  • 1Department of Orthodontics, Tianjin Medical University School and Hospital of Stomatology & Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration.

Abstract

Insights

The extracellular signal-regulated kinases (ERKs) pathway drives orthodontic tooth movement and bone remodeling, partly via STAT3. Targeting the ERKs/STAT3 axis may accelerate orthodontic treatment.

Area of Science:

  • Biomedical Engineering
  • Cell Biology
  • Orthodontics

Background:

  • Orthodontic tooth movement (OTM) involves complex mechanotransduction processes.
  • The role of the extracellular signal-regulated kinases (ERKs) pathway and its interaction with signal transducer and activator of transcription 3 (STAT3) in OTM is not fully understood.

Purpose of the Study:

  • To investigate the ERKs signaling pathway's role in orthodontic force-induced mechanotransduction and osteogenic differentiation.
  • To explore the crosstalk between ERKs and STAT3 in the context of OTM.

Main Methods:

  • In vitro: MC3T3-E1 cells subjected to cyclic tensile strain with or without an ERKs inhibitor (SCH772984).
  • In vivo: Mouse OTM model treated with SCH772984; analysis of pathway proteins, osteogenic markers, tooth movement, and bone microarchitecture.

Main Results:

  • Mechanical strain activated ERKs and STAT3 phosphorylation, upregulating osteogenic markers in vitro, effects inhibited by SCH772984.
  • In vivo, orthodontic force induced bone remodeling and OTM; SCH772984 suppressed ERKs activation and reduced tooth movement by approximately 40%.

Conclusions:

  • The ERKs pathway is crucial for orthodontic force-induced alveolar bone remodeling and OTM, partially mediated through STAT3.
  • The ERKs/STAT3 axis represents a potential therapeutic target for accelerating orthodontic treatments.

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
Notch Signaling Pathway03:14

Notch Signaling Pathway

The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...