Pathophysiology of calcium pyrophosphate deposition

2016 ◽  
Author(s):  
Abhishek Abhishek ◽  
Michael Doherty
Keyword(s):  
Dermatan Sulfate ◽  
Relative Concentration ◽  
Middle Layer ◽  
Calcium Pyrophosphate ◽  
Cartilage Matrix ◽  
Crystal Formation ◽  
Crystal Deposition ◽  
Inorganic Pyrophosphate ◽  
S 100 ◽  
Basic Calcium Phosphate Crystal

Calcium pyrophosphate (CPP) dihydrate crystals form extracellularly. Their formation requires sufficient extracellular inorganic pyrophosphate (ePPi), calcium, and pro-nucleating factors. As inorganic pyrophosphate (PPi) cannot cross cell membranes passively due to its large size, ePPi results either from hydrolysis of extracellular ATP by the enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (also known as plasma cell membrane glycoprotein 1) or from the transcellular transport of PPi by ANKH. ePPi is hydrolyzed to phosphate (Pi) by tissue non-specific alkaline phosphatase. The level of extracellular PPi and Pi is tightly regulated by several interlinked feedback mechanisms and growth factors. The relative concentration of Pi and PPi determines whether CPP or hydroxyapatite crystal is formed, with low Pi/PPi ratio resulting in CPP crystal formation, while a high Pi/PPi ratio promotes basic calcium phosphate crystal formation. CPP crystals are deposited in the cartilage matrix (preferentially in the middle layer) or in areas of chondroid metaplasia. Hypertrophic chondrocytes and specific cartilage matrix changes (e.g. high levels of dermatan sulfate and S-100 protein) are related to CPP crystal deposition and growth. CPP crystals cause inflammation by engaging with the NALP3 inflammasome, and with other components of the innate immune system, and is marked with a prolonged neutrophilic inflitrate. The pathogenesis of resolution of CPP crystal-induced inflammation is not well understood.

scholarly journals Upregulation of ANK Protein Expression in Joint Tissue in Calcium Pyrophosphate Dihydrate Crystal Deposition Disease

2013 ◽  
Vol 41 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Miwa Uzuki ◽  
Takashi Sawai ◽  
Lawrence M. Ryan ◽  
Ann K. Rosenthal ◽  
Ikuko Masuda
Keyword(s):  
Calcium Pyrophosphate ◽  
Calcium Pyrophosphate Dihydrate ◽  
Crystal Formation ◽  
Type X Collagen ◽  
Crystal Deposition ◽  
Chondrocyte Hypertrophy ◽  
Inorganic Pyrophosphate ◽  
Crystal Deposition Disease ◽  
Cppd Crystal ◽  
Pyrophosphate Dihydrate

Objective.Accumulation of excess extracellular inorganic pyrophosphate leads to calcium pyrophosphate dihydrate (CPPD) crystal formation in articular cartilage. CPPD crystal formation occurs near morphologically abnormal chondrocytes resembling hypertrophic chondrocytes. The ANK protein was recently implicated as an important factor in the transport of intracellular inorganic pyrophosphate across the cell membrane. We characterized ANK in joint tissues from patients with and without CPPD deposition and correlated the presence of ANK with markers of chondrocyte hypertrophy.Methods.Articular tissues were obtained from 24 patients with CPPD crystal deposition disease, 11 patients with osteoarthritis (OA) without crystals, and 6 controls. We determined the number of ANK–positive cells in joint tissues using immunohistochemistry and in situ hybridization, and correlated ANK positivity with markers of chondrocyte hypertrophy including Runx2, type X collagen, osteopontin (OPN), and osteocalcin (OCN).Results.ANK was detected in synoviocytes, chondrocytes, osteoblasts, and osteocytes. ANK was seen extracellularly only in the matrix of cartilage and meniscus. The number of ANK-positive cells was significantly higher in CPPD than in OA or normal joint tissues. The amount and intensity of ANK immunoreactivity reached maximum levels in the large chondrocytes around crystal deposits. ANK was similarly distributed to and significantly correlated with Runx2, type X collagen, OPN, and OCN.Conclusion.ANK levels were higher in articular tissues from patients with CPPD deposition. ANK was concentrated around crystal deposits and correlated with markers of chondrocyte hypertrophy. These findings support a role for ANK in CPPD crystal formation in cartilage.

The CPPDD-Associated ANKH M48T Mutation Interrupts the Interaction of ANKH with the Sodium/Phosphate Cotransporter PiT-1

2009 ◽  
Vol 36 (6) ◽  
pp. 1265-1272 ◽  
Author(s):  
JOHN WANG ◽  
HING WO TSUI ◽  
FRANK BEIER ◽  
FLORENCE W.L. TSUI
Keyword(s):  
Protein Interactions ◽  
Sodium Phosphate ◽  
Calcium Pyrophosphate ◽  
Calcium Pyrophosphate Dihydrate ◽  
Crystal Deposition ◽  
Inorganic Pyrophosphate ◽  
Expression Of Genes ◽  
Phosphate Treatment ◽  
Key Participants ◽  
High Phosphate

Objective.Numerous dominant human homolog of progressive ankylosis (ANKH) mutations have been identified in familial calcium pyrophosphate dihydrate crystal deposition disease (CPPDD). Due to the dominant nature of these mutations, we investigated whether ANKH interacts with other proteins; and if so, whether any CPPDD-associated ANKH mutation might disrupt such protein interactions.Methods.Stable ATDC5 ANKH wt- and ANKH M48T-transfectants were generated. Lysates from these transfectants were used to identify candidate protein interaction with ANKH by coimmunoprecipitation followed by Western blot analysis. The effect of high phosphate on the expression of genes involved in modulating Pi (inorganic phosphate)/PPi (inorganic pyrophosphate) homeostasis in these transfectants was assessed.Results.We showed that ANKH protein associates with the sodium/phosphate cotransporter PiT-1, and that ANKH M48T mutant protein failed to interact with PiT-1. We also showed that upon high phosphate treatment, the normally coordinated upregulation of endogenous Ank and PiT1 transcript expression was disrupted in ANKH M48T transfectants.ConclusionOur results suggested that there is a coordinated interrelationship between 2 key participants of Pi and PPi metabolism, ANKH and PiT-1.

scholarly journals THU0422 CALCIUM PYROPHOSPHATE CRYSTAL DEPOSITION WITHIN TOPHUS LOBULE: A FREQUENT ASSOCIATION OBSERVED IN LONG-TIME COURSE TOPHI

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 449.2-449
Author(s):  
H. K. Ea ◽  
O. Olivier ◽  
N. N. Pham ◽  
V. Frochot ◽  
D. Bazin ◽  
...  
Keyword(s):  
Time Course ◽  
Bone Erosion ◽  
Fibrous Tissue ◽  
Calcium Pyrophosphate ◽  
Small Sample ◽  
Disease Stage ◽  
Crystal Formation ◽  
Crystal Deposition ◽  
Long Time ◽  
Msu Crystals

Background:Calcium pyrophosphate (CPP) crystals and monosodium urate (MSU) crystals are frequently found in the same synovial fluids of gouty patients suggesting an interaction in crystal formation and deposition. This association has never been reported in tophus.Objectives:we aimed to describe the prevalence of CPP crystal deposition in tophus and to determine the associated risk factors.Methods:22 tophi consecutively harvested were fixed in 4% paraformaldehyde and embedded in paraffin. 5-µm thick sections were analyzed by compensated polarized microscopy (CPM) after hematoxylin and eosin staining. Characterization of CPP crystals were performed by scan electronic microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. Clinical characteristics were compared between patients having tophus with CPP deposition and patients having tophus without CPP crystals.Results:All tophi appeared multi-lobulated depositions of MSU crystals separated by fibrous tissue and surrounded by a foreign giant cell reaction. CPP crystals were identified in few lobules of 5 tophi (22.7%) harvested from 3 great toes, 1 elbow bursa and 1 finger of 5 patients. CPP crystals formed aggregate deposition within the lobule of MSU crystals. Both monoclinic and triclinic CPP crystal phases were identified by CPM, SEM and FTIR. Tophi were harvested from 22 male gouty patients with a mean age of 50.8 (28-66) years and a mean BMI of 24.2 kg/m2 (18.9-29.4). Mean serum urate level (SUL) was 499 ± 107 µmol/L. 59% of patients had chronic renal disease stage 2 or 3, 40.9% dyslipidemia, 22.7% type 2 diabetes mellitus, 13.6% hypertension and 50% obesity. Patients with tophi containing CPP deposition were older (61.2 [56-66] vs 47.8 [28-64] years, p=0.009) and had a longer gout duration (19 [10-31] vs 9 [3-20] years, p= 0.007) and tophus duration (11.4 [8-16] vs 4.5 [1-9] years, p< 0.0001) than patients with tophi alone. Tophi did not display calcification on radiographies performed before surgery. However, the density of tophi containing CPP crystal deposition was higher than the density of tophi without CPP crystals (51 [25-100] vs 21.5% [0-40], p=0.009). The proportion of bone erosion and gout arthropathy was similar between the two groups. Similarly, no difference was observed for SUL (467 ± 43 vs 509 ± 109 µmol/L), estimated glomerular filtration rate (76.6 ± 11.9 vs 74.9 ± 15.7 ml/min/1.73m2) and prevalence of comorbidities. Interestingly, no calcification was detected on knee and wrist radiographies of patients with tophi containing CPP deposition.Conclusion:These results reported for the first time, in a small sample size, that CPP crystal deposition occurred within tophus lobules. They suggested that long-time course tophi might act as a facilitating agent of CPP nucleation. This hypothesis needs specific confirmation studiesDisclosure of Interests: :None declared

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