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

Terkeltaub R - Purinergic Signal. (2006)

Bottom Line: 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).PP(i) generated by NPP1modulates not only hydroxyapatite crystal growth but also chondrogenesis and expression of the mineralization regulator osteopontin.

View Article: PubMed Central - PubMed

Affiliation: University of California School of Medicine, VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA, USA, rterkeltaub@ucsd.edu.

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.

No MeSH data available.


Related in: MedlinePlus

Proposed NPP1-mediated and PPi-dependent mechanisms stimulating CPPD and HA crystal deposition in aging and osteoarthritis (OA): Roles of ATP and PPi Metabolism and inorganic phosphate (Pi) generation in pathologic cartilage calcification. This model presents mechanisms underlying the common association of extracellular PPi excess with both CPPD and HA crystal deposition in OA and chondrocalcinosis cartilages, as well as the paradoxical association of extracellular PPi 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 PPi 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 PPi derived largely from cartilage. NPP1 not only directly induces elevated PPi but also matrix calcification by chondrocytes in vitro. Depending on extracellular availability of substrate PPi 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 PPi also may result from heightened release of intracellular PPi 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 PPi generation and release mediated via NPP1 and ANK, and diminished responsiveness to IGF-I, which normally suppresses elevation of chondrocyte extracellular PPi.
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Fig2: Proposed NPP1-mediated and PPi-dependent mechanisms stimulating CPPD and HA crystal deposition in aging and osteoarthritis (OA): Roles of ATP and PPi Metabolism and inorganic phosphate (Pi) generation in pathologic cartilage calcification. This model presents mechanisms underlying the common association of extracellular PPi excess with both CPPD and HA crystal deposition in OA and chondrocalcinosis cartilages, as well as the paradoxical association of extracellular PPi 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 PPi 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 PPi derived largely from cartilage. NPP1 not only directly induces elevated PPi but also matrix calcification by chondrocytes in vitro. Depending on extracellular availability of substrate PPi 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 PPi also may result from heightened release of intracellular PPi 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 PPi generation and release mediated via NPP1 and ANK, and diminished responsiveness to IGF-I, which normally suppresses elevation of chondrocyte extracellular PPi.

Mentions: Notably, PPi serves as reservoir for alkaline phosphatase-catalyzed Pi generation that is pro-mineralizing, as illustrated by osteopenia in long bones of NPP1 deficient mice [27, 28]. As such, PPi generation can both suppress and promote HA crystal deposition, depending on relative tissue levels of NPP1 and alkaline phosphatase (Figure 2) [16–21, 27, 28]. The capacity of chondrocytes to produce copious extracellular PPi is particularly double edged, as it is directly promotes calcium pyrophosphate dihydrate (CPPD) crystal deposition (Figure 2). Depending on cartilage ATP and PPi concentrations, and the level of activity of Pi-generating ATPases and pyrophosphatases, NPP1 excess promotes both HA and CPPD crystal formation by articular chondrocytes [12, 29–31], an event that commonly occurs in the joint in human aging and osteoarthritis (OA) [32].Figure 2


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

Terkeltaub R - Purinergic Signal. (2006)

Proposed NPP1-mediated and PPi-dependent mechanisms stimulating CPPD and HA crystal deposition in aging and osteoarthritis (OA): Roles of ATP and PPi Metabolism and inorganic phosphate (Pi) generation in pathologic cartilage calcification. This model presents mechanisms underlying the common association of extracellular PPi excess with both CPPD and HA crystal deposition in OA and chondrocalcinosis cartilages, as well as the paradoxical association of extracellular PPi 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 PPi 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 PPi derived largely from cartilage. NPP1 not only directly induces elevated PPi but also matrix calcification by chondrocytes in vitro. Depending on extracellular availability of substrate PPi 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 PPi also may result from heightened release of intracellular PPi 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 PPi generation and release mediated via NPP1 and ANK, and diminished responsiveness to IGF-I, which normally suppresses elevation of chondrocyte extracellular PPi.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2254483&req=5

Fig2: Proposed NPP1-mediated and PPi-dependent mechanisms stimulating CPPD and HA crystal deposition in aging and osteoarthritis (OA): Roles of ATP and PPi Metabolism and inorganic phosphate (Pi) generation in pathologic cartilage calcification. This model presents mechanisms underlying the common association of extracellular PPi excess with both CPPD and HA crystal deposition in OA and chondrocalcinosis cartilages, as well as the paradoxical association of extracellular PPi 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 PPi 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 PPi derived largely from cartilage. NPP1 not only directly induces elevated PPi but also matrix calcification by chondrocytes in vitro. Depending on extracellular availability of substrate PPi 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 PPi also may result from heightened release of intracellular PPi 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 PPi generation and release mediated via NPP1 and ANK, and diminished responsiveness to IGF-I, which normally suppresses elevation of chondrocyte extracellular PPi.
Mentions: Notably, PPi serves as reservoir for alkaline phosphatase-catalyzed Pi generation that is pro-mineralizing, as illustrated by osteopenia in long bones of NPP1 deficient mice [27, 28]. As such, PPi generation can both suppress and promote HA crystal deposition, depending on relative tissue levels of NPP1 and alkaline phosphatase (Figure 2) [16–21, 27, 28]. The capacity of chondrocytes to produce copious extracellular PPi is particularly double edged, as it is directly promotes calcium pyrophosphate dihydrate (CPPD) crystal deposition (Figure 2). Depending on cartilage ATP and PPi concentrations, and the level of activity of Pi-generating ATPases and pyrophosphatases, NPP1 excess promotes both HA and CPPD crystal formation by articular chondrocytes [12, 29–31], an event that commonly occurs in the joint in human aging and osteoarthritis (OA) [32].Figure 2

Bottom Line: 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).PP(i) generated by NPP1modulates not only hydroxyapatite crystal growth but also chondrogenesis and expression of the mineralization regulator osteopontin.

View Article: PubMed Central - PubMed

Affiliation: University of California School of Medicine, VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA, USA, rterkeltaub@ucsd.edu.

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.

No MeSH data available.


Related in: MedlinePlus