Physiologic and pathologic functions of the NPP nucleotide pyrophosphatase/phosphodiesterase family focusing on NPP1 in calcification

Abstract

The catabolism of ATP and other nucleotides participates partly in the important function of nucleotide salvage by activated cells and also in removal or de novo generation of compounds including ATP, ADP, and adenosine that stimulate purinergic signaling. Seven nucleotide pyrophosphatase/phosphodiesterase NPP family members have been identified to date. These isoenzymes, related by up conservation of catalytic domains and certain other modular domains, exert generally non-redundant functions via distinctions in substrates and/or cellular localization. But they share the capacity to hydrolyze phosphodiester or pyrophosphate bonds, though generally acting on distinct substrates that include nucleoside triphosphates, lysophospholipids and choline phosphate esters. PP(i) generation from nucleoside triphosphates, catalyzed by NPP1 in tissues including cartilage, bone, and artery media smooth muscle cells, supports normal tissue extracellular PP(i) levels. Balance in PP(i) generation relative to PP(i) degradation by pyrophosphatases holds extracellular PP(i) levels in check. Moreover, physiologic levels of extracellular PP(i) suppress hydroxyapatite crystal growth, but concurrently providing a reservoir for generation of pro-mineralizing P(i). Extracellular PP(i) levels must be supported by cells in mineralization-competent tissues to prevent pathologic calcification. This support mechanism becomes dysregulated in aging cartilage, where extracellular PP(i) excess, mediated in part by upregulated NPP1 expression stimulates calcification. PP(i) generated by NPP1modulates not only hydroxyapatite crystal growth but also chondrogenesis and expression of the mineralization regulator osteopontin. This review pays particular attention to the role of NPP1-catalyzed PP(i) generation in the pathogenesis of certain disorders associated with pathologic calcification.

Figure 1

General Structural Features of NPP family members. The schematic highlights related structural features of NPPs 1Y7, as discussed further in the text.

Figure 2

Proposed NPP1-mediated and PP_i-dependent mechanisms stimulating CPPD and HA crystal deposition in aging and osteoarthritis (OA): Roles of ATP and PP_i Metabolism and inorganic phosphate (P_i) generation in pathologic cartilage calcification. This model presents mechanisms underlying the common association of extracellular PP_i excess with both CPPD and HA crystal deposition in OA and chondrocalcinosis cartilages, as well as the paradoxical association of extracellular PP_i deficiency (from defective ANK or PC-1/NPP1 expression) with pathologic calcification of articular cartilage with HA crystals in vivo. Factors driving pathologic calcification are indicated in green and physiologic factors suppressing calcification in red. Excess PP_i generation in aging cartilages in idiopathic CPPD deposition disease of aging, and in OA cartilages, is mediated in part by marked increases in NTPPPH activity, mediated in large part by the PC-1/NPP1 isoenzyme. In idiopathic chondrocalcinosis of aging and in OA, there are substantial increases in joint fluid PP_i derived largely from cartilage. NPP1 not only directly induces elevated PP_i but also matrix calcification by chondrocytes in vitro. Depending on extracellular availability of substrate PP_i and the activity of pyrophosphatases, the availability of substrate ATP and the activity of ATPases, and other factors such as substantial local Mg⁺⁺ concentrations, HA crystal deposition, as opposed to CPPD deposition, may be stimulated. In this model, excess extracellular PP_i also may result from heightened release of intracellular PP_i via increased ANK expression in OA and abnormal ANK function in familial chondrocalcinosis, as well as from deficient activity of pyrophosphatases (such as TNAP and possibly inorganic pyrophosphatase) in certain primary metabolic disorders. Also illustrated at the top of this schematic is the role in cartilage calcification in OA and aging of altered TGFβ expression and responsiveness, which drives PP_i generation and release mediated via NPP1 and ANK, and diminished responsiveness to IGF-I, which normally suppresses elevation of chondrocyte extracellular PP_i.