Epithelial PCSK6 Promotes Proliferation and Decreases Collagen Deposition by Fibroblasts Potentially via MMP Activation

  • Int J Mol Sci. 2026 Jun 4;27(11):5104. doi: 10.3390/ijms27115104.
Qian Tian  1 ,  Annemiek Dijkhuis  1 ,  Ester B M Remmerswaal  1 ,  Hella Aberson  2 ,  Bruno Crestani  3 ,  Tom van der Poll  2  4 ,  C Arnold Spek  2  5 ,  Jan Willem Duitman  1  6  7
Affiliations
  • 1. Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
  • 2. Center for Infection and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
  • 3. Service de Pneumologie, Allergologie et Transplantation, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.
  • 4. Division of Infectious Diseases, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
  • 5. Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
  • 6. Department of Pulmonary Medicine, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
  • 7. Amsterdam Institute for Immunology & Infectious Disease, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
PMID: 42278627 DOI: 10.3390/ijms27115104
Abstract

A recent genome-wide association study showed that the protease proprotein convertase subtilisin/kexin type 6 (PCSK6) is highly expressed in idiopathic pulmonary fibrosis (IPF) lung parenchyma and that its expression is associated with disease progression and worse survival. However, whether PCSK6 plays a role in IPF pathophysiology remains elusive. This study aimed to determine whether PCSK6 contributes to IPF pathophysiology, specifically in the cross-talk between epithelial cells and fibroblasts. A549 epithelial cells were transduced with a PCSK6-GFP or control-mCherry vector. Both proliferation (crystal violet) and cell competition assays showed that PCSK6 promoted cell proliferation. Western blot and PCSK-specific fluorogenic substrate assays showed that A549-PCSK6 conditioned medium (CM) had higher PCSK6 enzyme activity compared to mCherry control A549 CM. Human lung fibroblasts stimulated with PCSK6-CM significantly decreased Collagen I protein levels as compared to fibroblasts stimulated with control A549-CM. Matrix-metalloproteinase (MMP) specific fluorogenic substrate assays subsequently showed that A549-PCSK6 CM contained higher MMP activity and that PCSK6 inhibition reduced MMP activity in A549-PCSK6 CM, suggesting that PCSK6 plays a role in the activation of MMPs that may degrade Collagen type I. In conclusion, epithelial PCSK6 promotes cell proliferation and decreases Collagen deposition by fibroblasts, potentially via MMP activation. These in vitro data suggest that PCSK6 could play a dual role in IPF progression and its actual role in IPF should consequently be elucidated using in vivo/ex vivo models.

Keywords
alveolar epithelial cells; idiopathic pulmonary fibrosis; lung fibroblasts; matrix metalloproteinases; proprotein convertase subtilisin/kexin type 6.
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