Key result
Knockdown or genetic deletion of TERT prevented calcification in vitro and in vivo, demonstrating its non-canonical role in initiating osteogenic reprogramming via STAT5 and RUNX2.
Why the study?
The initial steps in aortic valve leaflet osteogenic reprogramming are not fully understood, leading investigators to examine whether TERT contributes to valve interstitial cell osteogenic reprogramming.
TERT promotes calcific aortic valve disease through a non-canonical, STAT5-dependent pathway that initiates osteogenic reprogramming, identifying a potential therapeutic target.
TERT inhibition emerges as a candidate strategy in calcific aortic valve disease; hypothesis-generating in animal models and leaves open human translation.
BACKGROUND: Calcific aortic valve disease is the pathological remodeling of valve leaflets. The initial steps in valve leaflet osteogenic reprogramming are not fully understood. As TERT (telomerase reverse transcriptase) overexpression primes mesenchymal stem cells to differentiate into osteoblasts, we investigated whether TERT contributes to the osteogenic reprogramming of valve interstitial cells. METHODS: Human control and calcific aortic valve disease aortic valve leaflets and patient-specific human aortic valve interstitial cells were used in in vivo and in vitro calcification assays. Loss of function experiments in human aortic valve interstitial cells and cells isolated from Tert −/− and Terc −/− mice were used for mechanistic studies. Calcification was assessed in Tert +/+ and Tert −/− mice ex vivo and in vivo. In silico modeling, proximity ligation, and coimmunoprecipitation assays defined novel TERT interacting partners. Chromatin immunoprecipitation and cleavage under targets and tagmentation sequencing defined protein-DNA interactions. RESULTS: TERT protein was highly expressed in calcified valve leaflets without changes in telomere length, DNA damage, or senescence markers, and these features were retained in isolated primary human aortic valve interstitial cells. TERT expression increased with osteogenic or inflammatory stimuli, and knockdown or genetic deletion of TERT prevented calcification in vitro and in vivo. Mechanistically, TERT was upregulated via NF-κB (nuclear factor-kappa B) and required to initiate osteogenic reprogramming, independent of its canonical reverse transcriptase activity and the long noncoding RNA TERC . TERT exerts non-canonical osteogenic functions via binding with STAT5 (signal transducer and activator of transcription 5). Depletion or inhibition of STAT5 prevented calcification. STAT5 was found to bind the promoter region of RUNX2 (runt-related transcription factor 2), the master regulator of osteogenic reprogramming. Finally, we demonstrate that TERT and STAT5 are upregulated and colocalized in calcific aortic valve disease tissue compared with control tissue. CONCLUSIONS: TERT’s non-canonical activity is required to initiate calcification. TERT is upregulated via inflammatory signaling pathways and partners with STAT5 to bind the RUNX2 gene promoter. These data identify a novel mechanism and potential therapeutic target to decrease vascular calcification.
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Cuevas et al. (2025) studied Calcific aortic valve disease. TERT knockdown or genetic deletion vs. Control (Tert+/+ or wild-type) was evaluated on Calcification in vitro and in vivo. Knockdown or genetic deletion of TERT prevented calcification in vitro and in vivo, demonstrating its non-canonical role in initiating osteogenic reprogramming via STAT5 and RUNX2.
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