Concerted Regulation of Inorganic Pyrophosphate and Osteopontin by Akp2, Enpp1, and Ank

Harmey, Dympna; Hessle, Lovisa; Narisawa, Sonoko; Johnson, Kristen; Terkeltaub, Robert; Millán, José Luis

doi:10.1016/s0002-9440(10)63208-7

Cited by 460 publications

(533 citation statements)

References 40 publications

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“…Several human and mouse diseases with excessive or insufficient bone formation have been related to defects in, respectively, the phosphodiesterases (such as nucleotide pyrophosphatase/phosphodiesterase 1), which produce PPi (11,12), and the phosphatases (such as tissue-nonspecific alkaline phosphatase [TNAP]), which degrade PPi (13)(14)(15). The homozygous ank (progressive ankylosis) mouse has a loss-of-function nonsense mutation in the ank gene that codes for a regulator of PPi export, and these mice develop a condition characterized by pathologic calcium apatite crystal deposition in the synovial and subsynovial spaces, followed by chondro-osteophyte formation and eventual bony ankylosis of the affected joints (16).…”

Section: Conclusion Our Results Indicate That the Tnap Haplotype Rs3mentioning

confidence: 99%

Association of a TNAP haplotype with ankylosing spondylitis

Tsui¹,

Inman²,

Reveille³

et al. 2007

Arthritis & Rheumatism

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Objective. To use a candidate gene approach to the identification of genetic markers that are significantly associated with ankylosing spondylitis (AS).Methods. We genotyped 201 multiplex AS families with 1 exonic and 5 intronic single-nucleotide polymorphisms (SNPs) in TNAP, the gene that encodes tissuenonspecific alkaline phosphatase, and performed family-based association analyses.Results. In our cohort of 201 multiplex AS families, the TNAP haplotype rs3767155 (G)/rs3738099 (G)/ rs1780329 (T) was significantly associated with AS (P ‫؍‬ 0.032 by additive model). Haplotype-Based Association Testing (HBAT) analyses of AS families in which both men and women were affected showed that the same TNAP haplotype was significantly associated with AS (P ‫؍‬ 0.002 by additive model). Using setafftrait code 1 0 0 in the HBAT program, testing specifically for affected men in AS families containing affected individuals of both sexes, this TNAP haplotype was also significantly associated with AS (P ‫؍‬ 0.001 by additive model). The HBAT -p option (haplotype permutation test) was used to compute the "exact" P value via a Monte Carlo method for each haplotype (haplotype permutation test) and for the minimum observed P value among the haplotypes (whole marker permutation using the minimal P test), and both P values were statistically significant (2-sided P value for haplotype rs3767155[G]/rs3738099 [G]/rs1780329 [T] ‫؍‬ 0.00059, the smallest observed P value among all the individual haplotype scores ‫؍‬ 0.003). Interestingly, this haplotype was not associated with AS in affected women from the same families.Conclusion. Our results indicate that the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) is a novel genetic marker in men that is significantly associated with AS in multiplex families containing affected individuals of both sexes.

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Section: Conclusion Our Results Indicate That the Tnap Haplotype Rs3mentioning

confidence: 99%

Association of a TNAP haplotype with ankylosing spondylitis

Tsui¹,

Inman²,

Reveille³

et al. 2007

Arthritis & Rheumatism

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“…However, since the intracellular pyrophosphate concentration is only in the micromolar range the relative contribution of ANK to extracellular pyrophosphate levels is likely to be smaller than the breakdown of ATP by NPPs [28]. At present, the biological role and function of ANK remains unclear.…”

Section: Generation and Regulation Of Extracellular Pyrophosphatementioning

confidence: 99%

“…Tissue non-specific alkaline phosphatase (TNAP) is the only alkaline phosphatase implicated in mineralisation and is the key enzyme involved in pyrophosphate breakdown [35,36]. Previous work has suggested that the opposing actions of NPP1 and TNAP may be critical in determining local extracellular phosphate and pyrophosphate levels [28,37]. Deletion or inactivation of one of these enzymes has a significant effect on the skeleton (see reviews [35,39]).…”

Section: Pyrophosphate As An Inhibitor Of Bone Mineralisationmentioning

confidence: 99%

“…These animals display abnormal pyrophosphate levels, joint calcification and destruction, impaired gait and vertebral fusion characteristic of ankylosing spondylitis [27]. Interestingly, a comparative study reported that the ectopic mineralisation in ank/ank mice is less severe than in Enpp1 -/-animals suggesting that NPP1 is more important in extracellular pyrophosphate generation [28].…”

Section: Ankmentioning

confidence: 99%

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Pyrophosphate: a key inhibitor of mineralisation

Orriss

Arnett

Russell

2016

Current Opinion in Pharmacology

145

105

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“…Osteopontin interacts with the αvβ3 integrin (Wozniak et al 2000) and mediates cell adhesion and differentiation, which in turn could alter cell phenotype and matrix mineralization. In osteoblasts, osteopontin production is coordinately regulated with elaboration of inorganic pyrophosphate, a potent inhibitor of hydroxyapatite crystal formation Harmey et al 2004). Thus, osteopontin may indirectly affect mineralization by altering levels of other crystal-regulating substances.…”

Section: Nih Public Accessmentioning

confidence: 99%

Osteopontin promotes pathologic mineralization in articular cartilage

et al. 2007

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Calcium pyrophosphate dihydrate (CPPD) crystals are commonly found in osteoarthritic joint tissues, where they predict severe disease. Unlike other types of calcium phosphate crystals, CPPD crystals form almost exclusively in the pericellular matrix of damaged articular cartilage, suggesting a key role for the extracellular matrix milieu in their development. Osteopontin is a matricellular protein found in increased quantities in the pericellular matrix of osteoarthritic cartilage. Osteopontin modulates the formation of calcium-containing crystals in many settings. We show here that osteopontin stimulates ATP-induced CPPD crystal formation by chondrocytes in vitro. This effect is augmented by osteopontin's incorporation into extracellular matrix by transglutaminase enzymes, is only modestly affected by its phosphorylation state, and is inhibited by integrin blockers. Surprisingly, osteopontin stimulates transglutaminase activity in cultured chondrocytes in a dose responsive manner. As elevated levels of transglutaminase activity promote extracellular matrix changes that permit CPPD crystal formation, this is one possible mechanism of action. We demonstrate the presence of osteopontin in the pericellular matrix of chondrocytes adjacent to CPPD deposits and near active transglutaminases. Thus, osteopontin may play an important role in facilitating CPPD crystal formation in articular cartilage. KeywordsOsteopontin; Calcium pyrophosphate dihydrate; Transglutaminase; Osteoarthritis Pathologic matrix mineralization is a common occurrence in joints affected by late stage osteoarthritis. Of synovial fluids sampled at the time of knee replacement, for example, 60% contain pathologic calcium-containing crystals (Derfus et al. 2002). Both calcium pyrophosphate dihydrate (CPPD) and hydroxyapatite-like basic calcium phosphate (BCP) crystals occur in osteoarthritic joints. Although the role that calcium-containing crystals play in osteoarthritis is not fully understood, there is ample evidence to suggest that these crystals are active participants in joint damage. In vitro, calcium-containing crystals induce the release of catabolic cytokines and proteases from synovial cells and chondrocytes (Cheung 2001). Clinically, their presence predicts increased severity of joint damage and more rapid progression of joint destruction (Ledingham et al. 1993;Nalbant et al. 2003).Corresponding Author: Ann K. Rosenthal, MD Rheumatology Section/ cc-111W Zablocki VA Medical Center 5000 W. National Ave. Milwaukee, WI 53295-1000 TEL: 414-384-2000ann.rosenthal@med.va.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply ...

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Concerted Regulation of Inorganic Pyrophosphate and Osteopontin by Akp2, Enpp1, and Ank

Cited by 460 publications

References 40 publications

Association of a TNAP haplotype with ankylosing spondylitis

Association of a TNAP haplotype with ankylosing spondylitis

Pyrophosphate: a key inhibitor of mineralisation

Osteopontin promotes pathologic mineralization in articular cartilage

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