Multifarious roles of metal elements in bone mineralization

Bone mineralization involves the deposition of inorganic on organic matter and the regulation of non-collagenous proteins expressed by functional cells in bone tissue, is a fundamental process during skeletal growth, remodeling, and regeneration. Metal elements are the main constitutive elements of bone minerals. It is worth noting that the distribution and effects of metal elements depend on their type and content throughout the body, suggesting that different metal elements can regulate bone mineralization in different ways. Various metal elements can directly modify calcium phosphate (Ca-phosphate) formation in the bone matrix through ion exchanging, coating, and doping. Additionally, metal elements regulate bone mineralization by targeting important signaling pathways, protein secretion, and the expression of genes involved in the proliferation, differentiation and migration of cells involved in bone. This review introduces the roles of metal elements commonly found in nature bone. It summarizes recent studies on the prominent role of Ca element, special roles of divalent metal elements, trivalent metal elements, metal elements with various valences, and new points of heavy metal elements in bone mineralization. We also discuss potential future research directions on the roles of metal/non-metal elements and their interactions in bone mineralization, offering the basis for future investigations for the development of advanced bone substitute materials and orthopedic implants.