New face of an old enzyme: Alkaline phosphatase may contribute to human tissue aging by inducing tissue hardening and calcification

Abstract

Tissue nonspecific alkaline phosphatase (AP) plays a well-known role in bone mineralization. This role was first suggested by a human AP deficiency disease, hypophosphatasia. Further studies with AP gene knockout mice have also suggested a role for AP in mineralization. However, AP is also expressed in other human tissues besides bone and cartilage, and this raises a question as to whether AP may also play a role in pathological mineralization such as dystrophic and vascular calcification. In vitro studies carried out in our laboratory indicate that a variety of cell types stably expressing membrane-bound AP can affect extracellular mineralization regardless of the tissue from which the cell lines originated (e.g. fibroblasts, vascular endothelial cells, or renal epithelial cells). This AP-mediated extracellular mineralization is both substrate/dependent and culture environment/dependent and may be consistent with a putative role for AP in pathological mineralization in tissues other than bone and cartilage. In this regard, it is interesting to note that high levels of AP are observed in vascular endothelia of small arterioles in brain and heart. It is probable that expression of AP in small arterioles of brain and heart may also contribute to the vascular hardening and calcification observed in humans. This in turn could be related to vascular aging, vascular disease, and the resultant weakening of and/or rupture of vessel walls.

Characterization of rat heart alkaline phosphatase isoenzymes and modulation of activity

“…Alkaline phosphatase (ALP; EC 3.1.3.1.; orthophosphoric-monoester phosphohydrolase, alkaline optimum) is ubiquitous in nature (from bacteria to humans); however, its physiological role and natural substrates remain largely unknown (1,2). The first established function of ALP is its role in bone mineralization (1)(2)(3).…”

“…The first established function of ALP is its role in bone mineralization (1)(2)(3). More recently, it has been proposed that ALP regulates lipid transport (4).…”

“…More recently, it has been proposed that ALP regulates lipid transport (4). ALP expression in vascular endothelia of small arterioles in the Characterization of rat heart alkaline phosphatase www.bjournal.com.br brain and heart, which normally do not mineralize, could contribute to vascular hardening and calcification that could, in turn, be related to vascular aging and vascular disease (1,5).…”

“…These calcified lesions contain not only various components associated with bone mineralization, such as ALP, but also inflammatory cells such as macrophages and lymphocytes. Although the mechanisms underlying valve calcification have not been established, recent data suggest that valve calcification is an active process, much like atherosclerosis, that is preceded by inflammation, lipid deposition and the accumulation of extracellular bone matrix proteins (1,(6)(7)(8)(9)(10)(11).…”

Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity

“…Given the high expression levels of these two genes in mineralized tissues, removal of PP i is expected to be a prerequisite for physiologic mineralization, and thus regulation of the expression and activities of these two proteins is likely central to the control of mineralization. Tnap (tissue-nonspecific alkaline phosphatase; also known as Akp2), a well characterized marker of the osteoblast lineage (24), is capable of hydrolyzing PP i into P i (25). In osteoblast cultures, Tnap is also responsible for the generation of P i from phosphate esters such as ␤-glycerophosphate (␤GP), 4 which is commonly used as a source of organic phosphate for mineralization (26).…”