Mechanism of Bone Mineralization

Abstract

Mineralized "hard" tissues of the skeleton possess unique biomechanical properties to support the body weight and movement and act as a source of essential minerals required for critical body functions. For a long time, extracellular matrix (ECM) mineralization in the vertebrate skeleton was considered as a passive process. However, the explosion of genetic studies during the past decades has established that this process is essentially controlled by multiple genetic pathways. These pathways regulate the homeostasis of ionic calcium and inorganic phosphate-two mineral components required for bone mineral formation, the synthesis of mineral scaffolding ECM, and the maintainence of the levels of the inhibitory organic and inorganic molecules controlling the process of mineral crystal formation and its growth. More recently, intracellular enzyme regulators of skeletal tissue mineralization have been identified. The current review will discuss the key determinants of ECM mineralization in bone and propose a unified model explaining this process.

Figure 1.

Model of bone mineralization. Serum calcium (Ca²⁺), inorganic phosphate (P_i) levels, and a mineral scaffolding collagen-rich extracellular matrix (ECM) are important determinants of bone mineralization. Alkaline phosphatase (ALPL), an ectoenzyme tethered to the osteoblast cell membrane, cleaves inorganic pyrophosphate (PP_i), a small, but potent mineralization inhibitor. This facilitates bone ECM mineralization in two ways: first, it reduces the level of a mineralization inhibitor, and second, in the process generates P_i, an activator of ECM mineralization. This coupled ALPL activity alters the P_i/PP_i ratio in the bone microenvironment to favor bone mineralization. Compact hierarchical assembly of collagen molecules in the fibrils and fibers results in both intra- and interfibrillar nanoscale gaps. These gaps are accessible by Ca²⁺ and P_i ions, but not by the large protein inhibitors of ECM mineralization. This may explain why there are mineral deposits both inside and in the gaps in between the collagen fibrils. Matrix vesicle (MV)–mediated mineralization may serve as an auxiliary mechanism for bone mineralization. These nanoscale vesicles carrying the intracellular mineralization-promoting enzymes bud off from the mineralizing cells. Enzymes like SMPD3 and phospholipases present inside the MVs may cleave the phospholipids (e.g., sphingomyelin [SM]) to generate phosphocholine, which in turn can be cleaved by another cytosolic enzyme PHOSPHO1 liberating free P_i. An increase of intravesicular P_i leads to its precipitation with Ca²⁺ to form the nascent hydroxyapatite (HA) crystals.