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PubMed1994

Probenecid inhibits transforming growth factor-beta 1 induced pyrophosphate elaboration by chondrocytes.

OBJECTIVE: The elaboration of excess extracellular inorganic pyrophosphate (ePPi) by cartilage contributes to calcium pyrophosphate dihydrate (CPPD) crystal deposition disease. Transforming growth factor-beta 1 (TGF beta 1) is the only defined physiologic stimulant of cartilage ePPi elaboration. The mechanism of ePPi generation by chondrocytes is unknown, but current evidence suggests that TGF beta 1 induced ePPi is made intracellularly. An active transport mechanism such as an anion transporter would then be necessary to export ePPi to the matrix where crystals form. We determined the effect of probenecid (PB), an anion transport inhibitor, on TGF beta 1 induced ePPi elaboration. METHODS: Porcine hyaline articular chondrocytes in high density monolayer cultures were exposed to serum-free media with and without TGF beta 1 and/or PB. ePPi was measured in the media after 48-96 h of exposure. Cell injury was measured by examining the release of 3H-deoxyglucose from chondrocytes. The activity of the ePPi generating ectoenzyme nucleoside triphosphate pyrophosphohydrolase (NTPPPH) and media lactate concentrations were measured with standard colorimetric assays. As PB may inhibit phosphodiesterase (PDE), its effects on ePPi generation were compared with isobutylmethylxanthine (IBMX), a specific PDE inhibitor. RESULTS: PB inhibited TGF beta 1 induced ePPi elaboration by chondrocytes. PB did not cause membrane injury or decrease NTPPPH activity. Lactate production was decreased by PB but did not correlate with the effects of PB on ePPi elaboration. IBMX did not inhibit TGF beta 1 effect on ePPi elaboration. CONCLUSION: PB blocks TGF beta 1 induced ePPi elaboration. This effect is independent of cell membrane injury, decreased NTPPPH activity, or PDE inhibition. Our data implicate a role for anion transport in TGF beta 1 induced ePPi elaboration, and suggest a potential therapy for CPPD disease.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Overexpression, purification, and characterization of recombinant human 5-phosphoribosyl-1-pyrophosphate synthetase isozymes I and II.

Human 5-phosphoribosyl-1-pyrophosphate synthetase isozymes I and II (PRSI and PRSII) have been isolated independently and characterized in pure form. cDNAs for PRSI and PRSII were overexpressed in an Escherichia coli strain which lacks the bacterial 5-phosphoribosyl-1-pyrophosphate synthetase. The recombinant isoforms were purified to virtual homogeneity with specific activities of 25.0 and 35.7 units/mg, respectively, values which are 5-10-fold higher than any previously reported for this enzyme from human sources. Despite 95% amino acid sequence identity, the isoforms differed significantly in several physical and kinetic properties. PRSII was more sensitive to heat inactivation at 55 degrees C and more susceptible to disaggregation to inactive forms in the absence of Mg2+ and ATP than was PRSI. The isoforms were separable on the basis of isoelectric point. PRSI and PRSII also differed significantly in Km values for MgATP and ribose 5-phosphate, pH optima, and Mg2+ and Pi activation curves. PRSII was less sensitive to feedback inhibition by purine nucleotides and more sensitive to inhibition by 2,3-diphosphoglycerate than PRSI. Differences in kinetic properties between PRSI and PRSII are consistent with the suggestion that PRSII predominates in rapidly proliferating cells.

Adenosine Diphosphate↗
PubMed1993

Purification of a mammalian protein geranylgeranyltransferase. Formation and catalytic properties of an enzyme-geranylgeranyl pyrophosphate complex.

A protein geranylgeranyltransferase (PGGT) that transfers the geranylgeranyl group from geranylgeranyl pyrophosphate (GGPP) to the cysteine residue in the C-terminal sequence Cys-Ali-Ali-Leu (Ali is an aliphatic amino acid) of proteins and peptides has been purified to apparent homogeneity from bovine brain. This was accomplished by affinity chromatography of partially purified enzyme on a gel containing a covalently attached hexapeptide SSCILL. This peptide was identified as a tight-binding ligand of the PGGT by employing a semi-random peptide synthetic strategy. The purified enzyme consists of two subunits of apparent molecular mass 40 and 48 kDa. Affinity-purified PGGT effectively catalyzes the prenylation of peptides that contain a C-terminal Leu or Phe residue. The PGGT forms a stable binary complex with intact GGPP that can be isolated by gel filtration. Addition of a peptide substrate to this complex results in the quantitative transfer of the prenyl group to the peptide. This transfer occurs without the equilibration of enzyme-bound GGPP with free GGPP. When the PGGT was incubated with farnesyl pyrophosphate, the amount of binary complex formed was about 25% of that formed with GGPP.

Alkyl and Aryl Transferases↗
PubMed1994

Efficacy of a dentifrice containing potassium nitrate, soluble pyrophosphate, PVM/MA copolymer, and sodium fluoride on dentinal hypersensitivity: a twelve-week clinical study.

The effect on dentinal hypersensitivity from the use of a dentifrice containing 5.0% potassium nitrate, 1.3% soluble pyrophosphate, 1.5% PVM/MA copolymer, and 0.243% sodium fluoride in a silica base over a twelve-week period was compared to a matching placebo dentifrice without potassium nitrate. A total of sixty-seven subjects were entered into the study, and stratified into two balanced groups according to their baseline mean thermal (threshold) temperature (Thermodontic Stimulator) and baseline mean tactile (Yeaple Probe) sensitivity scores. The two groups were randomly assigned to use either the potassium nitrate/copolymer/pyrophosphate dentifrice or the placebo dentifrice. The two groups were well balanced with regard to their mean baseline thermal and tactile sensitivity scores, sex and age. Subjects were instructed to brush their teeth twice daily (morning and evening) for one minute with their assigned dentifrice and a commercially available soft-bristled toothbrush. Dentinal hypersensitivity examinations, which included tactile sensitivity, threshold thermal sensitivity, pain thermal sensitivity, air blast, and a visual analog scale were conducted at baseline, six weeks, and twelve weeks. All examinations were conducted by the same dental examiner. After six weeks' use of their assigned products, those subjects in the potassium nitrate/copolymer/pyrophosphate dentifrice group demonstrated statistically significant improvements (p < 0.01), as compared to the placebo dentifrice, in the following parameters: 1) tactile; 2) thermal (threshold and pain); and 3) air blast. After twelve weeks' use of their assigned products, those subjects in the potassium nitrate/copolymer/pyrophosphate dentifrice group again demonstrated statistically significant improvements (p < 0.01), in tactile, thermal (threshold and pain) and air blast sensitivity, as compared to the placebo dentifrice. It was concluded from this study that a dentifrice containing 5.0% potassium nitrate, 1.3% soluble pyrophosphate, 1.5% PVM/MA copolymer, and 0.243% sodium fluoride in a silica base is a clinically effective treatment for reducing dentinal hypersensitivity.

Adult↗
PubMed1977

In vitro technetium-99m red blood cell labeling using commercial stannous pyrophosphate.

A simple and rapid technique of preparing technetium-99m-labeled erythrocytes using commercial stannous pyrophosphate as the reducing agent was developed. The technique involves incubating red cells with stannous pyrophosphate, centrifugation, and addition of Tc-99m pertechnetate to the red cell fraction. A mean red cell labeling efficiency of 94% was achieved in 10 patient samples and less than 5% in vitro dissolution of Tc-99m red blood cells occurred up to two hours after preparation.

Drug Stability↗
PubMed1996

[Synthesis and properties of mixed ribodeoxyribooligonucleotide duplexes containing an internucleotide trisubstituted pyrophosphate bond].

Fragments of double-stranded RNAs and mixed double-stranded ribo/deoxyribooligonucleotides containing an internucleotide trisubstituted pyrophosphate bond in a predetermined position of the sugar-phosphate backbone were synthesized. The modified internucleotide bond was created between synthetic oligonucleotides by chemical ligation with carbodiimide. The chemical ligation conditions were optimized for a series of duplexes that differed in the content and mutual arrangement of ribo- and deoxyribonucleotide blocks. The yield of oligonucleotides containing the trisubstituted internucleotide pyrophosphate bond was 90% in an all-deoxy duplex and 15-68% in ribooligonucleotide-containing duplexes. The modified duplexes thus obtained are relatively stable in an aqueous solution at pH 5.5-7.5, whereas the modified internucleotide bond is cleaved by amines to form phosphamide derivatives of the corresponding oligonucleotides. Automated solid-phase synthesis of oligonucleotide 3'-ethylphosphates is described.

Base Sequence↗
PubMedDate not supplied

Intramolecular pyrophosphate formation during N alpha-9-fluorenylmethyloxycarbonyl (Fmoc) solid-phase synthesis of peptides containing adjacent phosphotyrosine residues.

The derivative N alpha-9-fluorenylmethyloxycarbonyl-O-phospho-L-tyrosine [Fmoc-Tyr(PO3H2)-OH] has been used successfully for the solid-phase synthesis of a wide variety of phosphorylated peptides. However, when it is used to incorporate consecutive phosphotyrosine residues, a pyrophosphate linkage can form between the two adjacent tyrosines. Incorporation of unprotected phosphotyrosine during the synthesis of peptides with multiple phosphotyrosine residues has been studied as a function of coupling conditions and the absence or presence of intervening amino acid residues. The pyrophosphate-forming side reaction is more severe with increased coupling times and/or repetitions of coupling and occurs only when the phosphotyrosine residues are directly adjacent to one another.

Amino Acid Sequence↗
PubMed1997

Anticalculus efficacy of an essential oil dentifrice containing 1.3% pyrophosphate ion.

One-hundred and fifty (150) healthy adult subjects, who readily form dental calculus under normal brushing conditions, completed this study to determine the efficacy of an essential oil dentifrice formulation containing 1.3% pyrophosphate ion (PPi) in inhibiting the development of supragingival calculus, compared to a commercially available control dentifrice (Crest Regular). This study was conducted in two phases: an 8-week pre-trial phase (Phase I) to identify a suitable calculus forming population, and a 12-week trial phase (Phase II) utilizing a randomized, double-blind, parallel group design. Calculus scores from Phase I were used to form balanced groups for Phase II. At the start of Phase I, subjects received a thorough dental prophylaxis and were instructed to brush twice daily for 60 seconds with the control dentifrice. At 8 weeks, subjects were scored for calculus; subjects with a Volpe-Manhold Calculus Index score > or = 7.0 qualified to enter Phase II. Qualifying subjects were stratified by calculus scores and randomly assigned to one of two treatment groups. Subjects then received a baseline oral soft tissue examination and dental prophylaxis, and began twice-daily brushing with their assigned dentifrice for 12 weeks. At 12 weeks, subjects received an oral soft tissue examination and were re-scored for calculus. The 1.3% PPi dentifrice group mean score was statistically significantly different (p = 0.03) from the control dentifrice group mean score, producing a 14.1% calculus reduction. In this study the essential oil dentifrice containing 1.3% pyrophosphate ion was effective in inhibiting the development of supragingival calculus.

Adult↗
PubMed1998

Safety and efficacy of a novel tartar control dentifrice containing 3.3% pyrophosphate: a controlled six-month clinical trial.

This study was undertaken to establish the tartar control efficacy and long-term safety of a new tartar control dentifrice that was formulated to enhance aesthetics and consumer acceptability. In a partially randomized, examiner-blind clinical trial, the experimental dentifrice, Crest MultiCare with 3.3% pyrophosphate, was compared to two currently marketed control dentifrices, Crest Regular Paste or Crest Tartar Protection Paste with 5.0% pyrophosphate. The eight-month trial model included a two-month pretest period to establish calculus formation after prophylaxis, followed by a six-month test period to evaluate efficacy and safety. Following the pretest period, 456 subjects were allocated to one of the three treatment groups and then monitored for calculus accumulation. After three and six months' test product use, the Crest MultiCare group experienced reductions in calculus accumulation of 28.9% and 32.3%, respectively compared to the regular control dentifrice. Over the six-month observation period, the experimental tartar control and the marketed tartar control dentifrices were comparable on adverse event frequency, type or severity, and no subject discontinued treatment due to an oral soft tissue adverse event. In this partially randomized and controlled six-month clinical trial, this new dentifrice exhibited tartar control efficacy, with a comparable overall safety profile to a marketed tartar control dentifrice.

Adult↗
PubMed1987

Chondrocalcinosis of the temporomandibular joint. Calcium pyrophosphate dihydrate deposition disease.

A case of calcium pyrophosphate dihydrate (CPPD) arthropathy of the temporomandibular joint, seen in a 54-year-old woman, is reported. The patient presented an eight-year history of diffuse swelling with tenderness over the right preauricular region. Surgical exploration of the right temporomandibular joint disclosed calcified masses that were identified as CPPD crystalline materials by histologic and infrared spectrophotometric studies. The occurrence of CPPD arthropathy of the temporomandibular joint is very rare, and this is only the fourth report of such a case, to our knowledge.

Calcium Pyrophosphate↗
PubMed1996

Tumoral calcium pyrophosphate dihydrate deposition disease: cytopathologic findings on fine-needle aspiration.

Tumoral calcium pyrophosphate dihydrate deposition disease (CPPD) is a rare non-neoplastic entity which mimics primary or metastatic soft-tissue or skeletal malignancy. Fewer than a dozen cases have been reported in the literature with only histologic descriptions. We present cytologic findings of a unique case of CPPD in a 73-year-old black female with a history of end-stage renal disease. A fine-needle aspiration (FNA) was done on a 4 x 4-cm neck mass which was clinically thought to be malignant. Cytopathologic examination showed numerous macrophages with markedly distended cytoplasm and containing multiple yellowish-orange, short rhomboid crystals. These were strongly birefringent on polarized microscopy, consistent with CPPD crystals.

Aged↗
PubMed1998

Parathyroid hormone-related proteins is abundant in osteoarthritic cartilage, and the parathyroid hormone-related protein 1-173 isoform is selectively induced by transforming growth factor beta in articular chondrocytes and suppresses generation of extracellular inorganic pyrophosphate.

OBJECTIVE: Parathyroid hormone-related protein (PTHrP) is a major, locally expressed regulator of growth cartilage chondrocyte proliferation, differentiation, synthetic function, and mineralization. Because mechanisms that limit cartilage chondrocytes from maturing and mineralizing are diminished in osteoarthritis (OA), we studied PTHrP expression by articular chondrocytes. METHODS: PTHrP was studied in normal knee cartilage samples and cultured articular chondrocytes, and in cartilage specimens from knees with advanced OA, obtained at the time of joint replacement. RESULTS: PTHrP was more abundant in OA than in normal human knee articular cartilage. Both demonstrated PTH/PTHrP receptor expression. PTHrP 1-173, one of three alternatively spliced PTHrP isoforms, was exclusively expressed and induced by transforming growth factor beta in cultured chondrocytes. Chondrocytes mainly used the GC-rich P2 alternative promoter to express PTHrP messenger RNA. Inhibition by PTHrP 1-173, but not by PTHrP 1-146 or PTHrP 1-87, of inorganic pyrophosphate (PPi) elaboration suggested selective functional properties of the 1-173 isoform. Exposure to a neutralizing antibody to PTHrP increased PPi elaboration by articular chondrocytes. CONCLUSION: Increased expression of PTHrP, including the 1-173 isoform, has the potential to contribute to the pathologic differentiated functions of chondrocytes, including mineralization, in OA.

Adult↗
PubMed2000

Extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 mitogen-activated protein kinase signaling and activation of activator protein 1 and nuclear factor kappaB transcription factors play central roles in interleukin-8 expression stimulated by monosodium urate monohydrate and calcium pyrophosphate crystals in monocytic cells.

OBJECTIVE: Monosodium urate monohydrate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals cause acute gout and pseudogout, respectively. Because acute gout and pseudogout appear to be dependent on interleukin-8 (IL-8)-induced neutrophil ingress, this study was undertaken to define and compare how MSU and CPPD crystals stimulate IL-8 messenger RNA (mRNA) expression in mononuclear phagocytes. METHODS: MSU and CPPD crystal-induced mitogen-activated protein kinase (MAPK) signal transduction and IL-8 transcriptional activation were studied in human monocytic cells, using the THP-1 cell line. RESULTS: MSU and CPPD crystals (0.5 mg/ml) induced activation of c-Jun N-terminal kinase, extracellular signal-regulated kinase 1 (ERK-1)/ERK-2, and p38 MAPK pathways in THP-1 cells. Activation of the ERK-1/ERK-2 pathway was essential for MSU and CPPD crystal-induced IL-8 mRNA expression, whereas the p38 pathway played a greater role in IL-8 mRNA expression in response to CPPD crystals in comparison with MSU crystals. Both crystals induced the binding of nuclear factor kappaB (NF-kappaB), including the NF-kappaB complex c-Rel/RelA, and activator protein 1 (AP-1, including N-terminal phosphorylated c-Jun) to the IL-8 promoter. Both crystals induced transcriptional activation of the IL-8 promoter, which was dependent on activation of c-Rel/RelA and AP-1. Activation of the NF-IL-6 transcription factor played a lesser role. Finally, crystal-induced IL-8 promoter activation was mediated by activation of the ERK-1/ERK-2 pathway, as demonstrated by transfection of dominant-negative raf-1. CONCLUSION: These results indicate that ERK-1/ ERK-2 signaling and transcriptional activation through AP-1 and NF-kappaB are essential for the induction of IL-8 expression in mononuclear phagocytes in response to CPPD and MSU crystals.

Calcium Pyrophosphate↗
PubMed1979

Clearance of calcium pyrophosphate dihydrate crystals in vivo. I. Studies using 169Yb labeled triclinic crystals.

Synthetic triclinic calcium pyrophosphate dihydrate crystals were uniformly trace-labeled with Ytterbium-169 (169Yb), a pure gamma-emitting isotope with a halflife of 31 days. The solubility of the labeled crystals was similar to that of cold synthetic crystals. The clearance rate of labeled sterile crystals, sieved to obtain the desired size, was determined after injection of microgram quantities into 4 arthritic huuman and 3 normal adult rabbit joints and corrected by the observed rate of clearance of free 169Yb. The derived rate constants were then used to calculate the time required for half of the injected dose of CPPD to be cleared from the joint. Crystal clearance was found in all instances. Crystal removal from normal rabbit joints was much more rapid than from the much larger human arthritic joints and was inversely proportional to the size of the crystals injected.

Animals↗
PubMed1979

Quantification of human plasma inorganic pyrophosphate. II. Biologic variables.

Plasma inorganic pyrophosphate (PPi) levels rose predictably (28%) after vigorous systemic exercise and returned to baseline values after 30 minutes of rest. Plasma PPi levels were greater (36%) in femoral venous blood than in femoral arterial blood. Forearm muscular exercise, however, did not result in a detectable rise in plasma PPi levels in antecubital veins. The physiologic reasons for both the systemic exercise effect and the arteriovenous differences remain unknown. Measurement of plasma PPi for 10 consecutive days in a single normal subject under basal conditions, where these and other previously identified biologic variables (fasting and diurnal variation) were controlled, showed a coefficient of variation of 12.7%. Thus biologic variability contributed less to observed variation in plasma PPi than did methodologic errors (coefficient of variation of method = 8%). The striking reproducibility of plasma PPi in this subject suggests that this important metabolite is under rather tight homeostatic control.

Calcium Pyrophosphate↗
PubMed1979

CLearance of calcium pyrophosphate dihydrate crystals in vivo. II. Studies using triclinic crystals doubly labeled with 45Ca and 85Sr.

The clearance rate of isotopically labeled synthetic triclinic calcium pyrophosphate dihydrate (CPPD) crystals injection into rabbit joints was estimated by serial counting. Kinetic analysis using a four compartment model showed that half of the injected dose was cleared from 4 rabbit knee joints in 19.1 +/- 0.42 (SEM) days. Profound hypomagnesemia, produced in 2 rabbits with a low magnesium diet, did not affect the rate of crystal clearance detectably. Lavage of joints with solutions known to promote CPPD crystal solubility failed to remove detectable radioactivity. The previous finding of CPPD crystals in synovial phagocytes by electron microscopy, together with the finding of nuclide activity in the synovium and the failure to remove such activity by joint lavage, suggests that endocytosis by synovial cells is an important, effective mechanism controlling the synovial fluid concentration of crystals in patients with CPPD crystal deposition disease.

Animals↗
PubMed1981

Clearance of calcium pyrophosphate dihydrate crystals in vivo. III. Effects of synovial hemosiderosis.

Synthetic triclinic calcium pyrophosphate dihydrate crystals, uniformly labeled with 85Sr and 45Ca, were injected into the knee joints of 2 normal adult rabbits and 2 rabbits previously injected repeatedly with autologous blood. The "half clearance time" of the injected crystal mass was 20.4 and 19 days from control joints, nearly identical to previously reported values in 6 rabbits (19.1 +/- 1.4), and 28.8 and 34 days from the joints injected with blood, a significant difference (P less than 0.05). Iron stains showed hemosiderin granules in the superficial synovium in these joints. Electron microscopy showed crystals with a molar calcium/phosphorus ratio of 1.0 and particles containing iron within synovial cells. We hypothesize that the decreased clearance rate from hemosiderotic synovium is due to inhibition of one or more intracellular pyrophosphatases by iron.

Animals↗
PubMed1981

Release of collagenase, neutral protease, and prostaglandins from cultured mammalian synovial cells by hydroxyapatite and calcium pyrophosphate dihydrate crystals.

Hydroxyapatite (HA) and calcium pyrophosphate dihydrate (CPPD) crystals were phagocytosed when added to cultured human rheumatoid or normal canine synovial cells. Collagenase and neutral protease secretion into the culture medium was increased 5- to 8-fold over control values in the presence of HA and increased 3-fold in the presence of CPPD crystals. HA but not CPPD crystals induced a 300-fold increase in human rheumatoid synovial cell culture fluid prostaglandin (PG) E2 levels and an 8-fold increase in PGF alpha levels. This mechanism may be important in the pathogenesis of the destructive arthropathies associated with HA and CPPD crystals.

Animals↗