Phosphorylated Proteins and Control Over Apatite Nulcleation, Crystal Growth and Inhibition
By A. George, A. Veis. Chemical Reviews, 2008
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Living organisms are capable of inducing the crystallization and deposition of a wide variety of minerals1 but the vertebrates mainly utilize the calcium phosphates in constructing their mineral phases in both normal circumstances in bone, dentin and tooth enamel and in pathological ectopic mineral deposits. The predominant form of the mineral in all situations is as carbonated apatite. However, the extent of mineralization in a particular tissue or organ is quite variable and crystallite size, crystal shape, and the packing and organization of the mineral crystals may also be variable. It is clear that the same physical chemical principles must apply to all, but it is equally clear that the organism must tightly regulate the local environment where the mineral is formed. This is an intrinsically complex problem because the mineral crystals of bone and dentin form in the extracellular matrix, external to the cells which are the ultimate regulators of the process. Years of study of this complex set of problems has led to the general consensus that the cell-controlled processes of mineralization begin with the manufacture of an organic structure within which, or a compartment surface upon which, the mineral crystals may be initiated. The cells secrete and organize macromolecular structures which determine the ultimate character and orientations of the crystals subsequently initiated and grown, but in general, these structures do not themselves have the capacity to initiate mineralization. The incipient crystal nucleation event depends upon the interaction of the structural macromolecules with another set of secreted interactive macromolecules which locate specifically on the structural framework. These interactive molecules are doubly interactive, binding specifically to the framework on the one hand, and attracting the requisite mineral ions on the other to initiate the mineral ion clustering to a critical size that nucleates crystal growth. The biological fluids are supersaturated in mineral ion content with respect to the solubility of their biogenic mineral crystal phase, but unrestricted and uncontrolled crystal growth are not permissible in the vertebrate animal so there is a third line of macromolecular components interactive with the growing crystal surfaces that can limit growth rates, and do so selectively, controlling the crystal shape as well as size. A final component of the regulation is the availability of the crystal microions, pumped in controlled fashion from the cell into the extracellular matrix. The situation is shown schematically in Figure 1, wherein the solid, heavy arrows trace the construction of the structural matrix (a), the addition of the interactive macromolecules that activate the structural matrix (b) to bind the mineral ions (c), leading to growth of the oriented crystals (d), and finally, the addition of further macromolecules (e) to shape and delimit the crystal size to attain the mature mineralized matrix form. Note that in this paragraph, and in Figure 1 the nature of the macromolecules and mineral phase has not been specified. This is intentional to emphasize the point that in the majority of mineralizing tissues in animal systems the same overall scheme of events is likely to apply, although the structural scaffolds and mineral types can vary greatly. Figure 1 A proposed generalized scheme for matrix-regulated mineralization reactions. Modified and reprinted with permission from Reference 280 [Veis, Reviews in Mineralogy & Geochemistry, V. 54]. Copyright 2003 Mineralogical Society of America. The calcium and phosphate ion product (Ca × P) in the extracellular fluids (ECF) of the vertebrates are greater than the solubility products of most crystalline forms of calcium phosphate, with hydroxylapatite (HA) being the major least soluble form of calcium phosphate. Hence, HA would precipitate spontaneously if it were not for the inhibition of crystal formation by the reduction of the activity of these ions, and their sequestration, by various macromolecular components. Thus, the ECF proteins in Ca-rich milk and blood, for example, play important roles as inhibitors of apatite precipitation. The initial form of the Ca – P solid phase deposits in vitro have been shown to be disordered and exhibit a diffuse X-ray diffraction pattern, indicating that initially only a very short range ordering of calcium and phosphate ions relative to each other takes place, producing a structure called “amorphous calcium phosphate” (ACP) 2,3,4. Depending upon the conditions of temperature, pH, and ion concentrations, the solid phase may grow through a variety of forms from the ACP to (in order of decreasing solubility) brushite [CaHPO4·2H2O], whitlockite [Ca3(PO4)2 ·3H20], octacalcium phosphate [Ca8H2(PO4)6·5H2O], and hydroxyapatite [Ca10(PO4)6(OH)2]. In bone, dentin, cementum and enamel, in vivo, where the nucleation process and the final crystal composition are determined by the local environment created by the combination of the collagen or amelogenin structural matrix and particular NCP components, it is evident that the transition from ion aggregate to crystalline form is tightly regulated. A question of great importance for those interested in development of biomimetic models of bone is how the NCP might template the desired crystal forms. The principal focus of this review, however, will be on the influence of the phosphoproteins of the matrix on the formation and growth of crystals in two systems: the small, plate-like crystals and crystal aggregates of carbonated apatite found in bone, dentin and cementum; and the large, high axial ratio rod-like crystal aggregates found in dental enamel. As pointed out many years ago5, the dentin and enamel are formed in apposition to each other and provide direct contrasts between the nature of the compartments created by the cells, the structural matrices produced, and the extracellular matrix macromolecules that control the nucleation, growth and structure of their carbonated apatite mineral phases. Here we consider these two systems separately.
Subfields: Molecular Biology, Rheumatology, Urology
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Citations in the corpus
- Calcium Orthophosphates in Nature, Biology and Medicine (2009, background): “there is greater association with proteins, such as osteocalcin, that regulate remodeling [422].”
- Limitations in Bonding to Dentin and Experimental Strategies to Prevent Bond Degradation (2011, methodology): “Additional acidic matrix phosphoproteins are utilized as templates to induce mineral nucleation and growth within the organic scaffold (George and Veis, 2008).”
- The role of collagen in bone apatite formation in the presence of hydroxyapatite nucleation inhibitors (2010, background): “This process is believed to be directed by highly acidic non-collagenous protein”