Science and Research

Loss of LRP1 promotes acquisition of contractile-myofibroblast phenotype and release of active TGF-beta1 from ECM stores

In healing tissue, fibroblasts differentiate to alpha-smooth muscle actin (SMA)-expressing contractile-myofibroblasts, which pull the wound edges together ensuring proper tissue repair. Uncontrolled expansion of the myofibroblast population may, however, lead to excessive tissue scarring and finally to organ dysfunction. Here, we demonstrate that the loss of low-density lipoprotein receptor-related protein (LRP) 1 overactivates the JNK1/2-c-Jun-Fra-2 signaling pathway leading to the induction of alpha-SMA and periostin expression in human lung fibroblasts (hLF). These changes are accompanied by increased contractility of the cells and the integrin- and protease-dependent release of active transforming growth factor (TGF)-beta1 from the extracellular matrix (ECM) stores. Liberation of active TGF-beta1 from the ECM further enhances alpha-SMA and periostin expression thus accelerating the phenotypic switch of hLF. Global gene expression profiling of LRP1-depleted hLF revealed that the loss of LRP1 affects cytoskeleton reorganization, cell-ECM contacts, and ECM production. In line with these findings, fibrotic changes in the skin and lung of Fra-2 transgenic mice were associated with LRP1 depletion and c-Jun overexpression. Altogether, our results suggest that dysregulation of LRP1 expression in fibroblasts in healing tissue may lead to the unrestrained expansion of contractile myofibroblasts and thereby to fibrosis development. Further studies identifying molecules, which regulate LRP1 expression, may provide new therapeutic options for largely untreatable human fibrotic diseases.

  • Schnieder, J.
  • Mamazhakypov, A.
  • Birnhuber, A.
  • Wilhelm, J.
  • Kwapiszewska, G.
  • Ruppert, C.
  • Markart, P.
  • Wujak, L.
  • Rubio, K.
  • Barreto, G.
  • Schaefer, L.
  • Wygrecka, M.

Keywords

  • Contractility
  • Extracellular matrix
  • Fibrosis
  • Low-density lipoprotein receptor-related protein 1
  • Phenotypic switch
Publication details
DOI: 10.1016/j.matbio.2019.12.001
Journal: Matrix Biol
Work Type: Original
Location: UGMLC
Disease Area: DPLD
Partner / Member: JLU, MPI-BN
Access-Number: 31841706
See publication on PubMed

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