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Updated: Feb 1, 2026
Isolation and Characterization of Primary Rat Valve Interstitial Cells: A New Model to Study Aortic Valve Calcification
Published on: November 20, 2017
Treatment with XAV-939 prevents in vitro calcification of human valvular interstitial cells
Claudia Dittfeld1, Gabriel Reimann1, Alice Mieting1
1Technische Universität Dresden, Faculty of Medicine Carl Gustav Carus, Department of Cardiac Surgery, Herzzentrum Dresden, Dresden, Germany.
Abstract:
The development of a substance or inhibitor-based treatment strategy for the prevention of aortic valve stenosis is a challenge and a main focus of medical research in this area. One strategy may be to use the tankyrase inhibitor XAV-939, which leads to Axin stabilisation and subsequent destruction of the β-catenin complex and dephosphorylation of β-catenin. The dephosphorylated active form of β-catenin (non-phospho-β-catenin) then promotes nuclear transcription that leads to osteogenesis. The aims of the present study were to develop an experimental system for inducing in vitro calcification of human aortic valvular interstitial cells (VICs) to investigate the potential anti-calcific effect of XAV-939 and to analyse expression of the Wnt signalling proteins and Sox9, a chondrogenesis regulator, in this model. Calcification of human VIC cultures was induced by cultivation in an osteogenic medium and the effect of co-incubation with 1μM XAV-939 was monitored. Calcification was quantified when mineral deposits were visible in culture and was histologically verified by von Kossa or Alizarin red staining and by IR-spectroscopy. Protein expression of alkaline phosphatase, Axin, β-catenin and Sox9 were quantified by western blotting. In 58% of the VIC preparations, calcification was induced in an osteogenic culture medium and was accompanied by upregulation of alkaline phosphatase. The calcification induction was prevented by the XAV-939 co-treatment and the alkaline phosphatase upregulation was suppressed. As expected, Axin was upregulated, but the levels of active non-phospho-β-catenin were also enhanced. Sox9 was induced during XAV-939 treatment but apparently not as a result of downregulation of β-catenin signalling. XAV-939 was therefore able to prevent calcification of human VIC cultures, and XAV-939 treatment was accompanied by upregulation of active non-phospho-β-catenin. Although XAV-939 does not downregulate active β-catenin, treatment with XAV-939 results in Sox9 upregulation that may prevent the calcification process.
Insights
The tankyrase inhibitor XAV-939 prevents aortic valve calcification in human cells. This study shows XAV-939 inhibits osteogenesis and upregulates Sox9, offering a potential therapeutic strategy for aortic valve stenosis.
Area of Science:
- Biomedical research
- Cardiovascular pathology
- Molecular biology
Background:
- Aortic valve stenosis (AVS) prevention is a key research area, with substance or inhibitor-based strategies being a focus.
- The Wnt/β-catenin signaling pathway plays a role in osteogenesis, a process implicated in AVS.
- Tankyrase inhibitors, such as XAV-939, stabilize Axin, leading to β-catenin destruction and potentially inhibiting osteogenesis.
Purpose of the Study:
- To establish an in vitro system for inducing calcification in human aortic valvular interstitial cells (VICs).
- To investigate the anti-calcific potential of the tankyrase inhibitor XAV-939 in this model.
- To analyze the expression of Wnt signaling proteins and Sox9, a chondrogenesis regulator, under XAV-939 treatment.
Main Methods:
- Human VICs were cultured in osteogenic medium to induce calcification.
- Co-incubation with 1μM XAV-939 was used to assess its effect on calcification.
- Calcification was quantified using von Kossa and Alizarin red staining, and IR-spectroscopy. Protein expression (alkaline phosphatase, Axin, β-catenin, Sox9) was analyzed by western blotting.
Main Results:
- Osteogenic medium successfully induced calcification in 58% of VIC preparations, with increased alkaline phosphatase.
- XAV-939 treatment prevented calcification and suppressed alkaline phosphatase upregulation.
- XAV-939 upregulated Axin and active non-phospho-β-catenin, and induced Sox9 expression, independent of β-catenin downregulation.
Conclusions:
- XAV-939 effectively prevents in vitro calcification of human aortic valvular interstitial cells.
- The anti-calcific effect of XAV-939 is associated with Sox9 upregulation, suggesting a novel mechanism.
- XAV-939 presents a potential therapeutic agent for preventing aortic valve stenosis.
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