Nucleic Acids as Emerging Regulators of Calcium Phosphate Biomineralization

Calcium phosphate biomineralization is a highly regulated process that underlies the formation of vertebrate mineralized tissues. While proteins have long been recognized as the principal regulators of mineral formation, accumulating experimental evidence suggests that nucleic acids may also contribute to this process through mechanisms that remain largely unexplored. Their negatively charged phosphate backbone, molecular structural versatility, and ability to interact with calcium phosphate phases make nucleic acids attractive candidates for regulating mineral nucleation, growth, and phase transformations. In this review, we first summarize the current understanding of physiological calcium phosphate biomineralization, with particular emphasis on the roles of collagen and matrix vesicles in mineral formation as well as factors influencing this process. We then examine the mechanism by which nucleic acids interact with calcium phosphate, highlighting experimental evidence demonstrating nucleic acid adsorption, coprecipitation, and mineral templating. Finally, we discuss the growing evidence supporting the presence of extracellular nucleic acids within mineralized tissues and ectopic mineralization, their diverse biological origins, and their potential contribution to pathological mineralization through mechanisms involving bacteria, extracellular vesicles, cell death, and neutrophil extracellular traps. These observations suggest that nucleic acids should be considered as potential contributors to calcium phosphate biomineralization. Although their precise physiological functions remain poorly understood, integrating nucleic acids into current mechanistic models may refine our understanding of both physiological and pathological mineralization processes, thus opening new avenues for biomarker discovery and therapeutic investigations.