Runx2 (Runt-Related Transcription Factor 2) Links the DNA Damage Response to Osteogenic Reprogramming and Apoptosis of Vascular Smooth Muscle Cells

Objective: The development of ectopic vascular calcification is strongly linked with organismal aging, which is primarily caused by the accumulation of DNA damage over time. As Runx2 (Runt-related transcription factor 2) has been identified as a regulator of vascular smooth muscle cell osteogenic transition, a key component of vascular calcification, we examined the relationship between DNA damage and Runx2 activation. Approach and Results: We found genotoxic stress-stimulated Runx2 accumulation and transactivation of its osteogenic target genes, leading to enhanced calcification. Inhibition of DNA damage signaling attenuated this response. Runx2 localized to sites of DNA damage and participated in DNA repair by regulating phosphorylation events on histone H2AX, with exogenous expression of Runx2 resulting in unrepaired DNA damage and increased apoptosis. Mechanistically, Runx2 was PARylated in response to genotoxic stress, and inhibition of this modification disrupted its localization at DNA lesions and reduced its binding to osteogenic gene promoters. Conclusions: These data identify Runx2 as a novel component of the DNA damage response, coupling DNA damage signaling to both osteogenic gene transcription and apoptosis and providing a mechanism for accelerated mineralization in aging and chronic disease.