MMP-12-Induced Pro-osteogenic Responses in Human Aortic Valve Interstitial Cells

J Surg Res. 2019 Mar;235:44-51. doi: 10.1016/j.jss.2018.09.005. Epub 2018 Oct 23.

Abstract

Background: Calcific aortic valve disease (CAVD) is an age-related and slowly progressive valvular disorder. Overexpression of matrix metalloproteinase 12 (MMP-12) has been found in atherosclerosis, stiffed vascular tissue, and calcified aortic valves. We hypothesized that MMP-12 may induce the pro-osteogenic responses in human aortic valve interstitial cells (AVICs).

Methods: Human AVICs were isolated from normal and calcified aortic valves. Cells were treated with MMP-12. The pro-osteogenic marker Runt-related transcription factor 2 (RUNX-2), bone morphogenetic protein 2 (BMP-2), and alkaline phosphatase (ALP), as well as MMP-12-associated signaling molecules, were analyzed.

Results: Human calcified aortic valves expressed significantly higher MMP-12 than normal human aortic valves. MMP-12-induced the expression of RUNX-2, BMP-2, ALP, and calcium deposit formation. Suppression of MMP-12 by its inhibitor decreased the expression of RUNX-2, BMP-2, and ALP. MMP-12-induced osteogenic responses were associated with higher levels of phosphorylation of p38 mitogen-activated protein kinases (MAPK), low density lipoprotein-related protein 6 (LRP-6), and β-catenin signaling molecules. Calcified aortic valves exhibited markedly higher levels of LRP-6 and β-catenin levels. Inhibition of either p38 MAPK or LRP-6 attenuated MMP-12-induced expression of RUNX-2, BMP-2, and ALP. Suppression of p38 MAPK abrogated MMP-12-induced activation of LRP-6 and β-catenin signaling pathways.

Conclusions: MMP-12 induces pro-osteogenic responses in AVICs by activation of p38 MAPK-mediated LRP-6 and β-catenin signaling pathways. The study revealed that the potential role of MMP-12 in the pathogenesis of CAVD and therapeutically targeting MMP-12 may suppress the development of CAVD.

Keywords: Aortic valve; MMP-12; Pro-osteogenic proteins; Signal transduction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aortic Valve / cytology*
  • Aortic Valve / metabolism
  • Aortic Valve / pathology
  • Aortic Valve Stenosis / etiology
  • Aortic Valve Stenosis / metabolism
  • Bone Morphogenetic Protein 2 / physiology
  • Calcinosis / etiology
  • Calcinosis / metabolism
  • Cells, Cultured
  • Female
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / physiology
  • Male
  • Matrix Metalloproteinase 12 / physiology*
  • Middle Aged
  • Osteogenesis / physiology*
  • Signal Transduction
  • beta Catenin / physiology
  • p38 Mitogen-Activated Protein Kinases / physiology

Substances

  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • CTNNB1 protein, human
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • beta Catenin
  • p38 Mitogen-Activated Protein Kinases
  • MMP12 protein, human
  • Matrix Metalloproteinase 12

Supplementary concepts

  • Aortic Valve, Calcification of