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Canonical and noncanonical TGF-β signaling regulate fibrous tissue differentiation in the axial skeleton

Sade W Clayton1, Ga I Ban1,2, Cunren Liu1

  • 1Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, 660 MCLM, 1918 University Blvd., Birmingham, Al, 35294-0005, USA.

Scientific Reports
|December 8, 2020
PubMed

Insights

Transforming growth factor-beta (TGF-β) regulates fibrous connective tissue development in the spine. TGF-β signaling involves ERK1/2 and Scleraxis, with Smad3 cooperating to control Fibromodulin and Adamtsl2 expression.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Transforming growth factor-beta (TGF-β) signaling is crucial for embryonic development.
  • Previous studies linked TGF-β type 2 receptor to fibrous connective tissue integrity in the spine.
  • The precise molecular mechanisms of TGF-β in sclerotome fibrous differentiation remain incompletely understood.

Purpose of the Study:

  • To elucidate the signaling pathways by which TGF-β regulates key fibrous matrix genes in the mouse sclerotome.
  • To identify the roles of canonical (Smad3) and noncanonical (ERK1/2) pathways in TGF-β-mediated gene expression.
  • To determine the potential involvement of Scleraxis as an intermediate in TGF-β signaling.

Main Methods:

  • Treatment of mouse sclerotome cells with TGF-β.
  • Quantitative analysis of Scleraxis, Fibromodulin, and Adamtsl2 mRNA expression.
  • Investigation of protein synthesis requirements using cycloheximide.
  • Assessment of Smad3 and ERK1/2 pathway involvement via genetic manipulation or inhibitors.
  • Analysis of gene expression in Smad3-deficient and ERK1/2-inhibited contexts.

Main Results:

  • TGF-β rapidly stimulated Scleraxis mRNA and, with a delay, Fibromodulin and Adamtsl2 mRNA.
  • Scleraxis regulation by TGF-β was protein synthesis-independent, while Fibromodulin and Adamtsl2 required it.
  • Scleraxis acts as an intermediate for TGF-β-induced Fibromodulin and Adamtsl2 expression.
  • ERK1/2 activation by TGF-β was essential for regulating all three fibrous markers.
  • Smad3 was not required for Scleraxis regulation but was necessary for Fibromodulin and Adamtsl2 expression.

Conclusions:

  • A novel TGF-β signaling cascade in sclerotome involves ERK1/2 activation leading to Scleraxis expression.
  • Scleraxis, in conjunction with Smad3, subsequently drives the expression of Fibromodulin and Adamtsl2.
  • This pathway defines a new mechanism for TGF-β in controlling fibrous differentiation during spine development.

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