MMP-12–Induced pro-osteogenic responses in human aortic valve interstitial cells
Open accessAbstract
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.
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MMP12 was shown to induce pro-osteogenic responses in human aortic valve interstitial cells.
“Moreover, it was shown to induce pro-osteogenic responses in human aortic valve interstitial cells 30 .”
From Sex-specific gene expression signatures of calcific aortic valve stenosis in a large collection of human tissues (2026) · cites this paper as [30]
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- Authors
- Deng, X.-S., Meng, X., Li, F., Venardos, N., Fullerton, D., & Jaggers, J.
- Affiliations
- Children's Hospital Colorado (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Jaggers, James
- Venue
- Journal of Surgical Research
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 235
- Pages
- 44-51
- ISSN
- 0022-4804 (ISSN-L)
- PMC
- PMC6791591
- OpenAlex
- W2896894415
- Cited by
- 24
- References
- 28
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 4
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Surgical Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health,United States (RO1 HL106582)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Keywords
- MMP-12, calcific aortic valve disease, aortic valve interstitial cells, osteogenic differentiation, Runx2, BMP-2, alkaline phosphatase, p38 MAPK, β-catenin signaling, valve calcification, MMP-12 inhibitors
- MeSH terms
- Aged, Aortic Valve, Aortic Valve Stenosis, Calcinosis, Cells, Cultured, Female, Humans, Male, Middle Aged, Osteogenesis, Signal Transduction, p38 Mitogen-Activated Protein Kinases, beta Catenin, Matrix Metalloproteinase 12, Bone Morphogenetic Protein 2, Low Density Lipoprotein Receptor-Related Protein-6
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