Redox proteomics gives insights into the role of oxidative stress in alkaptonuria

Braconi, Daniela; Millucci, Lia; Ghezzi, Lorenzo; Santucci, Annalisa

doi:10.1586/14789450.2013.858020

Cited by 23 publications

(18 citation statements)

References 120 publications

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“…The presence of HGA in AKU tissues has been shown to increase oxidative stress on cells [25][26][27]59]; this involvement of changes in the antioxidant defences is also seen in OA with both IL-1β and IL-6 shown to dysregulate antioxidant defences in chondrocytes [60]. The significance of the IL-6 results presented in this study, showing a significant increase in pigmentation compared to HGA and IL-6 alone presented in this study, are supported by clinical evidence that there is a significant increase in serum IL-6 in AKU patients compared to control [61].…”

Section: Discussionmentioning

confidence: 99%

“…One factor that has been shown to be increased as far as ochronosis is concerned is the oxidative stress encountered by cells in AKU patient tissues [25][26][27][28]. However, the presence of HGA alone cannot be the sole factor in causing the pigmentation given that HGA is present systemically, if not from birth, hours or days shortly after for many years prior to joint manifestations caused by ochronosis.…”

Section: Introductionmentioning

confidence: 99%

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A role for interleukins in ochronosis in a chondrocyte in vitro model of alkaptonuria

et al. 2015

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Alkaptonuria is a rare autosomal recessive condition resulting from inability to breakdown homogentisic acid (HGA), an intermediate in tyrosine degradation. The condition has a triad of clinical features, the most damaging of which is ochronotic osteoarthropathy. HGA is elevated from birth, but pigmentation takes many years. We hypothesise that interleukins play a role in initiation and progression of ochronotic osteoarthropathy. C20/A4 cells were cultured and maintained in 9-cm petri dishes containing either HGA at 0.33 mM, a single interleukin (IL-1β, IL-6 or IL-10) at 1 ng/ml or a combination of HGA and a single interleukin. Statistical analysis of pigment deposits and cell viability was performed using analysis of variance with Newman-Keuls post-test. All cultures containing HGA showed a significant increase in pigment deposition compared to control and IL cultures alone. The cultures containing HGA and IL-6 showed a significant increase in pigment deposits compared to HGA alone. The cell viability counts across all cultures on day 10 demonstrated a significant decrease in cultures containing HGA compared to those which did not. There was no significant difference between cultures containing just HGA or those combined with an interleukin. This work demonstrates a role for cytokines present in the joint(s) in the pigmentation process, particularly IL-6, and that the presence of HGA in joint tissues appears more detrimental to chondrocytes than the presence of any of the interleukins found in response to joint injury, trauma and osteoarthritis (OA). This further supports the evidence that the arthropathy in alkaptonuria is much more severe and rapidly progressing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A role for interleukins in ochronosis in a chondrocyte in vitro model of alkaptonuria

et al. 2015

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“…The local expression of HGD in human osteoarticular system dramatically increases the effects in AKU cartilage degeneration. We also reported that plasma from AKU patients and an AKU human plasma model contains inflammatory cytokines, free radicals and oxidants acting as cytotoxic agents for chondrocytes (Tinti et al, 2011a;Braconi et al, 2012;Laschi 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%

“…Our previous work (Braconi et al, 2010a,b;Tinti et al, 2010;Tinti et al, 2011a,b;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). 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;.…”

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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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Inhibition of para‐Hydroxyphenylpyruvate Dioxygenase by Analogues of the Herbicide Nitisinone As a Strategy to Decrease Homogentisic Acid Levels, the Causative Agent of Alkaptonuria

et al. 2016

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Alkaptonuria (AKU) is a rare multisystem metabolic disease caused by deficient activity of homogentisate 1,2-dioxygenase (HGD), which leads to the accumulation of homogentisic acid (HGA). Currently, there is no treatment for AKU. The sole drug with some beneficial effects is the herbicide nitisinone (1), an inhibitor of p-hydroxyphenylpyruvate dioxygenase (4-HPPD). 1 has been used as a life-saving drug in infants with type I tyrosinemia despite severe side effects due to the buildup of tyrosine. Four clinical trials of nitisinone to treat AKU have shown that 1 consistently decreases HGA levels, but also caused the accumulation of tyrosine in blood serum. Moreover, the human preclinical toxicological data for 1 are incomplete. In this work, we performed pharmacodynamics and toxicological evaluations of 1, providing the first report of LD50 values in human cells. Intracellular tyrosinemia was also evaluated. Three additional 4-HPPD inhibitors with a more favorable profile than that of 1 in terms of IC50, LD50, and tyrosine accumulation were also identified among commercially available compounds. These may be promising starting points for the development of new therapeutic strategies for the treatment of AKU.

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Redox proteomics gives insights into the role of oxidative stress in alkaptonuria

Cited by 23 publications

References 120 publications

A role for interleukins in ochronosis in a chondrocyte in vitro model of alkaptonuria

A role for interleukins in ochronosis in a chondrocyte in vitro model of alkaptonuria

Chondroptosis in Alkaptonuric Cartilage

Inhibition of para‐Hydroxyphenylpyruvate Dioxygenase by Analogues of the Herbicide Nitisinone As a Strategy to Decrease Homogentisic Acid Levels, the Causative Agent of Alkaptonuria

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