Development of an in vitro model to investigate joint ochronosis in alkaptonuria

Tinti, Laura; Taylor, Adam Michael; Santucci, Annalisa; Wlodarski, Brenda; Wilson, Peter J.; Jarvis, Jonathan C.; Fraser, William D.; Davidson, John S.; Ranganath, L.; Gallagher, James A.

doi:10.1093/rheumatology/keq246

Cited by 61 publications

(62 citation statements)

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“…Oxidative stress is at the center of AKU pathophysiological scene and ROS injury is crucial in many degenerative diseases (Bocci and Valacchi, 2013; Signorini et al, 2014); oxidative stress is also related to HGA‐induced AKU chondrocyte apoptosis and cartilage degeneration, as we recently reported (Braconi et al, 2010a,b; Tinti et al, 2010, 2011a,2011b; Braconi et al, 2012; Laschi et al, 2012; Millucci et al, 2012; Braconi et al, 2013; Spreafico et al, 2013). There is growing evidence (Armstrong, 2002; Poli et al, 2008) that HNE, generated during the LPO process and here reported to be present in AKU chondroptotic cartilage (Fig.…”

Section: Discussionmentioning

confidence: 58%

“…Our previous work (Braconi et al, 2010,b; Tinti et al, 2010; Tinti et al, 2011a,2011b; Braconi et al, 2012; Laschi et al, 2012; Millucci et al, 2012; Braconi et al, 2013; Spreafico et al, 2013) suggested that morphological changes of chondrocytes in AKU cartilage may be attributed to apoptosis, but until now no in depth study exists to elucidate if chondroptosis may occur in AKU. Moreover, ultra‐structural observations were complemented with biochemical and proteomic characterization of chondrocytes isolated from the ochronotic cartilage of AKU patients, indicating that AKU chondrocytes are characterized by HGA‐induced apoptosis, protein aggregation, nitric oxide release, and oxidative stress (Tinti et al, 2011a; Laschi et al, 2012; Millucci et al, 2012; Braconi et al, 2013; Spreafico et al, 2013).…”

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confidence: 99%

“…Moreover, ultra‐structural observations were complemented with biochemical and proteomic characterization of chondrocytes isolated from the ochronotic cartilage of AKU patients, indicating that AKU chondrocytes are characterized by HGA‐induced apoptosis, protein aggregation, nitric oxide release, and oxidative stress (Tinti et al, 2011a; Laschi et al, 2012; Millucci et al, 2012; Braconi et al, 2013; Spreafico et al, 2013). AKU patients have high levels of plasma serum amyloid A and pro‐inflammatory cytokines (Tinti et al, 2011b; Laschi et al, 2012; Millucci et al, 2012; Braconi et al, 2013; Millucci et al, 2014). The local expression of HGD in human osteoarticular system (Laschi et al, 2012) dramatically increases the effects in AKU cartilage degeneration.…”

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confidence: 99%

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Chondroptosis in Alkaptonuric Cartilage

Millucci

Giorgetti

Viti

et al. 2015

Journal Cellular Physiology

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Alkaptonuria (AKU) is a rare genetic disease that affects the entire joint. Current standard of treatment is palliative and little is known about AKU physiopathology. Chondroptosis, a peculiar type of cell death in cartilage, has been so far reported to occur in osteoarthritis, a rheumatic disease that shares some features with AKU. In the present work, we wanted to assess if chondroptosis might also occur in AKU. Electron microscopy was used to detect the morphological changes of chondrocytes in damaged cartilage distinguishing apoptosis from its variant termed chondroptosis. We adopted histological observation together with Scanning Electron Microscopy and Transmission Electron Microscopy to evaluate morphological cell changes in AKU chondrocytes. Lipid peroxidation in AKU cartilage was detected by fluorescence microscopy. Using the above‐mentioned techniques, we performed a morphological analysis and assessed that AKU chondrocytes undergo phenotypic changes and lipid oxidation, resulting in a progressive loss of articular cartilage structure and function, showing typical features of chondroptosis. To the best of our knowledge, AKU is the second chronic pathology, following osteoarthritis, where chondroptosis has been documented. Our results indicate that Golgi complex plays an important role in the apoptotic process of AKU chondrocytes and suggest a contribution of chondroptosis in AKU pathogenesis. These findings also confirm a similarity between osteoarthritis and AKU. J. Cell. Physiol. 230: 1148–1157, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 58%

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confidence: 99%

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confidence: 99%

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Chondroptosis in Alkaptonuric Cartilage

Millucci

Giorgetti

Viti

et al. 2015

Journal Cellular Physiology

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“…In more recent years the defective gene has been mapped and cloned (Pollak et al 1993;Zatkova 2011). An in vitro model and a mouse model are also available to aid in understanding the progression of the disease and screening of therapeutic agents (Preston et al 2014;Taylor et al 2012;Tinti et al 2011). Although advances have been made in understanding AKU there is one area that is still somewhat lacking: the analysis and understanding of what occurs to HGA and the chemical changes that occur as it polymerises that may enable or determine how the pigment interacts with the cells and extracellular matrices of AKU patients' tissues.…”

Section: Introductionmentioning

confidence: 99%

“…The histological reaction of HGA and its polymeric derivative with Schmorl's reagent show identical staining properties to tyrosine and melanin (Tinti et al 2011). The conversion of L-tyrosine to its L-3,4-dihydroxyphenylalanine (L-DOPA) intermediary and melanin is catalysed by tyrosinase and it has been proposed that this could also be involved in the conversion of HGA to its quinone intermediary and subsequent ochronotic pigment (Taylor et al 2016a, b).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Melanin-like Pigment Synthesized from Homogentisic Acid, with or without Tyrosine, and Its Implications in Alkaptonuria

Taylor

Vercruysse

2016

JIMD Reports

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Alkaptonuria is an iconic disease used by Archibald Garrod to demonstrate the theory of "inborn errors of metabolism". AKU knowledge has advanced in recent years: development of an in vitro model, discovery of murine models and advances in understanding bone and cartilage phenotypes and arthropathy in AKU. These discoveries have aided in a new clinical trial into nitisinone. However, there are still knowledge gaps surrounding the pigment in AKU and the pigmentation process. We demonstrate an advance in the understanding in the kinetics and chemistry of the polymerisation of homogentisic acid (HGA) into its pigment using size-exclusion chromatography and IR spectroscopy. We compared the properties of HGA-based pigments that were freshly prepared to those stored in solution for 2 years. Our results demonstrate the importance of pH in the polymerisation process and that colour change seen in solution (analogous to AKU patient urine) is not initially due to presence of ochronotic pigment but the quinone intermediary. In addition, we observed that pigment formation from HGA can occur in the presence of tyrosine, without the inclusion of this tyrosine into the pigment. These observations have positive implications for patients with alkaptonuria; an increased understanding of the pigment polymer chemistry, the presence of an intermediary and their kinetics present more therapeutic opportunities for treating the condition, including preventing the pigment from forming, binding or reversing established pigmentation. AKU patients treated with nitisinone show elevated tyrosine levels causing side effects such as corneal opacities; our data demonstrates that elevated tyrosine levels should not contribute or add to the ochronotic pigment burden in these patients.

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Melanins as Sustainable Resources for Advanced Biotechnological Applications

et al. 2020

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Melanins are a class of biopolymers that are widespread in nature and have diverse origins, chemical compositions, and functions. Their chemical, electrical, optical, and paramagnetic properties offer opportunities for applications in materials science, particularly for medical and technical uses. This review focuses on the application of analytical techniques to study melanins in multidisciplinary contexts with a view to their use as sustainable resources for advanced biotechnological applications, and how these may facilitate the achievement of the United Nations Sustainable Development Goals.

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Development of an in vitro model to investigate joint ochronosis in alkaptonuria

Abstract: We have developed an in vitro model of ochronosis that should contribute to understanding joint destruction in AKU and to the aetiology of OA.

Cited by 61 publications

References 14 publications

Chondroptosis in Alkaptonuric Cartilage

Chondroptosis in Alkaptonuric Cartilage

Analysis of Melanin-like Pigment Synthesized from Homogentisic Acid, with or without Tyrosine, and Its Implications in Alkaptonuria

Melanins as Sustainable Resources for Advanced Biotechnological Applications

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