Calcium–Collagen Coupling is Vital for Biomineralization Schedule

Abstract Biomineralization is a chemical reaction that occurs in organisms in which collagen initiates and guides the growth and crystallization of matched apatite minerals. However, there is little known about the demand pattern for calcium salts and collagen needed by biomineralization. In this study, natural bone biomineralization is analyzed, and a novel interplay between calcium concentration and collagen production is observed. Any quantitative change in one of the entities causes a corresponding change in the other. Translocation‐associated membrane protein 2 (TRAM2) is identified as an intermediate factor whose silencing disrupts this relationship and causes poor mineralization. TRAM2 directly interacts with the sarcoplasmic/endoplasmic reticulum calcium ATPase 2b (SERCA2b) and modulates SERCA2b activity to couple calcium enrichment with collagen biosynthesis. Collectively, these findings indicate that osteoblasts can independently and directly regulate the process of biomineralization via this coupling. This knowledge has significant implications for the developmentally inspired design of biomaterials for bone regenerative applications.