Increased Pyrophosphate in Fibroblasts and Lymphoblasts from Patients with Hereditary Diffuse Articular Chondrocalcinosis

Lust, George; Fauré, G; Netter, Patrick; Seegmiller, J. Edwin

doi:10.1126/science.6270793

Cited by 34 publications

(9 citation statements)

References 16 publications

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“…Relative to the levels of wild‐type ANKH , we observed markedly enhanced expression in vitro of 2 of the familial and sporadic chondrocalcinosis ANKH mutants (+14‐bp C‐to‐T and C‐terminal deletion, respectively), and a lesser degree of increased expression of the −4‐bp G‐to‐A variant. The 143‐bp T‐to‐C variant, which was originally described more than 20 years ago in a French kindred (38, 39), was not associated with a significant increase in the levels of expression relative to wild‐type ANKH . The locations of the mutation in the 5′‐UTR, just after the start codon in exon 1, or right in front of the stop codon in the last exon of ANKH , have the potential to increase ANKH RNA ribosomal binding or stability, possibly explaining the increase in protein expression.…”

Section: Discussionmentioning

confidence: 92%

Association of sporadic chondrocalcinosis with a −4‐basepair G‐to‐A transition in the 5′‐untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate

Zhang¹,

Johnson²,

Russell³

et al. 2005

Arthritis & Rheumatism

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Objective. Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis.Methods. ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes.Results. Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5-untranslated region (5-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P ‫؍‬ 0.0006; overall genotype association P ‫؍‬ 0.02). This ؊4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (؉14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the ؊4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen.Conclusion. A subset of sporadic chondrocalcinosis appears to be heritable via a ؊4-bp G-to-A ANKH 5-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.

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Section: Discussionmentioning

confidence: 92%

Association of sporadic chondrocalcinosis with a −4‐basepair G‐to‐A transition in the 5′‐untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate

Zhang¹,

Johnson²,

Russell³

et al. 2005

Arthritis & Rheumatism

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“…One example is a prevalent disease of the elderly, idiopathic chondrocalcinosis, where the deposition in articular cartilage of calcium pyrophosphate dihydrate (CPPD) crystals is strongly linked to substantial increases in NTPPPH activity and PP1 concentration (14)(15)(16). A 2-to 3-fold increase in intracellular PPi has been found in cartilage cells, fibroblasts, and lymphoblasts cultured from chondrocalcinosis patients (17)(18)(19). The capacity of CPPD crystals to activate cells can promote acute and chronic inflammatory synovitis and cartilage degeneration (15,20).…”

mentioning

confidence: 99%

Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes.

Lotz

Rosen

McCabe

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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“…In this disease, the deposition of calcium pyrophosphate dihydrate (CPPD) crys-tals in articular cartilage is strongly linked to substantial increases in NTPPPH activity and PPi concentration (14)(15)(16). In addition, a 2-3-fold increase in intracellular PPi has been found in cartilage cells, fibroblasts, and lymphoblasts cultured from chondrocalcinosis patients (17)(18)(19). The capacity of CPPD crystals to activate cells can promote acute and chronic inflammatory synovitis and cartilage degeneration (15,20).…”

mentioning

confidence: 99%

Differential effects of aging on human chondrocyte responses to transforming growth factor β. Increased pyrophosphate production and decreased cell proliferation

Rosen¹,

McCabe²,

Quach³

et al. 1997

Arthritis & Rheumatism

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Objective. To address the influence of age on inorganic pyrophosphate (PPi) accumulation in human articular chondrocytes.Methods. Articular cartilage was obtained from men and women in 2 different age groups: ages 15-55 and 56-91. The effects of transforming growth factor Pl (TGFP1) on PPi levels in the media and cell lysates of chondrocytes were investigated. In addition, the effects of TGFP on PPi accumulation were compared with chondrocyte proliferation.Results. TGFPl increased PPi levels to a greater extent in chondrocytes from subjects in the older age group compared with those obtained from younger subjects. Treatment of chondrocytes with TGFPl led to a similar increase in total intracellular protein in both age groups. Although TGFP increased nucleoside triphosphate pyrophosphohydrolase activity and decreased alkaline phosphatase activity, these effects did not differ between the 2 age groups. Analysis of the same cell preparations showed an age-related decrease in TGFP-induced chondrocyte proliferation, whereas these same cells showed an increased response with respect to PPi elaboration.Conclusion. These results show that aging differentially affected TGFP-induced PPi accumulation ver-

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Increased Pyrophosphate in Fibroblasts and Lymphoblasts from Patients with Hereditary Diffuse Articular Chondrocalcinosis

Cited by 34 publications

References 16 publications

Association of sporadic chondrocalcinosis with a −4‐basepair G‐to‐A transition in the 5′‐untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate

Association of sporadic chondrocalcinosis with a −4‐basepair G‐to‐A transition in the 5′‐untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate

Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes.

Differential effects of aging on human chondrocyte responses to transforming growth factor β. Increased pyrophosphate production and decreased cell proliferation

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