Curr Opin Orthop 18:444–448.

Purpose of review
Alkaline phosphatase is an important component in hard tissue formation, highly expressed in mineralized tissue cells. It is appropriate to review the current status of this important enzyme.
Recent findings
The mechanism with which this enzyme carries out its function is not completely understood, but it appears to act both to increase the local concentration of inorganic phosphate, a mineralization promoter, and to decrease the concentration of extracellular pyrophosphate, an inhibitor of mineral formation. The enzyme is localized to the outside of the plasma membrane of cells, and of the membrane of matrix vesicles. It is attached to the membrane by a glycophosphatidylinositol anchor, and is found in membrane microdomains known as rafts. Alkaline phosphatase has also been implicated in cardiovascular calcification which appears to proceed by an osteogenic mechanism. Significant interest in alkaline phosphatase expression has also come from tissue engineering experiments, where enzyme expression is a good predictor of neotissue mineralization.
Summary
The high level of activity in this field is sure to provide new and important information into the fundamental mechanisms of hard tissue formation, provide therapeutic opportunities for treatment of bone diseases, and enhance our ability to create useful bone biomaterials.

J Nippon Med Sch. 2010 Feb;77(1):4-12.
Biomineralization is the process by which hydroxyapatite is deposited in the extracellular matrix. Physiological mineralization occurs in hard tissues, whereas pathological calcification occurs in soft tissues. The first step of mineralization is the formation of hydroxyapatite crystals within matrix vesicles that bud from the surface membrane of hypertrophic chondrocytes, osteoblasts, and odontoblasts. This is followed by propagation of hydroxyapatite into the extracellular matrix and its deposition between collagen fibrils. Extracellular inorganic pyrophosphate, provided by NPP1 and ANKH, inhibits hydroxyapatite formation. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes pyrophosphate and provides inorganic phosphate to promote mineralization. Inorganic pyrophosphate, pyridoxal phosphate, and phosphoethanolamine are thought to be the physiologic substrates of TNAP. These accumulate in the event of TNAP deficiency, e.g., in cases of hypophosphatasia. The gene encoding TNAP is mapped to chromosome 1, consists of 12 exons, and possesses regulatory motifs in the 5′-untranslated region. Inhibition of TNAP enzymatic activity suppresses TNAP mRNA expression and mineralization in vitro. Hypophosphatasia is an inherited systemic bone disease characterized by hypomineralization of hard tissues. The phenotype of hypophosphatasia is varied. To date, more than 200 mutations in the TNAP gene have been reported. Knockout mice mimic the phenotypes of severe hypophosphatasia. Among the mutations in the TNAP gene, c.1559delT is frequent in the Japanese population. This frameshift mutation results in the expression of an abnormally long protein that is degraded in cells. DNA-based prenatal diagnosis using chorionic villus sampling has been developed, but requires thorough genetic counseling. Although hypophosphatasia is untreatable at present, the recent success of enzyme replacement therapy offers promise. The problems presented by impaired mineralization in age-related chronic diseases, such as pathologic calcification and decreasing physiological mineralization are growing in importance. Strategies for preventing pathologic calcification using TNAP and NPP1 are in development. A nutrigenomic approach, based on the relationship between TNAP gene polymorphism and bone mineral density, is also discussed.