Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone

Preston, Andrew J; Keenan, Craig; Sutherland, Hazel; Wilson, Peter J.; Wlodarski, Brenda; Taylor, Adam Michael; Williams, Dominic P.; Ranganath, L.; Gallagher, James A.; Jarvis, Jonathan C.

doi:10.1136/annrheumdis-2012-202878

Cited by 90 publications

(112 citation statements)

References 26 publications

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“…Midlife treatment with 4 mg/L nitisinone from 34 to 81 weeks of age suppressed plasma HGA concentration by approximately 15-fold, in agreement with previous work (Preston et al 2014) (Fig. 1b).…”

Section: Resultssupporting

confidence: 92%

“…Ochronosis has recently been described in two murine models of AKU (Taylor et al 2012;Preston et al 2014). In the latter of the two models, we have described the efficacy of nitisinone in treating ochronosis in a murine model of AKU and demonstrated that lifetime administration of nitisinone reduced plasma HGA by 88% and prevented ochronotic pigment deposition in the tibiofemoral joint (Preston et al 2014). This was the first time that inhibition of ochronosis by nitisinone had been demonstrated and highlighted the efficacy of nitisinone as a treatment for AKU.…”

Section: Introductionmentioning

confidence: 93%

“…Plasma HGA concentration was determined via HPLC as described previously (Preston et al 2014), on a Phenomenex Kinetex XB-C18 column, 2.6 mM (4.6 Â 100 mm). Briefly, the initial mobile phase was 100% buffer A (12 mM orthophosphoric acid, Sigma, UK), before increasing buffer B (100% methanol, Sigma, UK) from 0 to 80% over 10 min.…”

Section: Chromatographic Conditionsmentioning

confidence: 99%

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Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice

et al. 2015

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Alkaptonuria (AKU) is an ultrarare autosomal recessive disorder resulting from a deficiency of homogentisate 1,2 dioxygenase (HGD), an enzyme involved in the catabolism of phenylalanine and tyrosine. Loss of HGD function prevents metabolism of homogentisic acid (HGA), leading to increased levels of plasma HGA and urinary excretion. Excess HGA becomes deposited in collagenous tissues and subsequently undergoes polymerisation, principally in the cartilages of loaded joints, in a process known as ochronosis. This results in an early-onset, devastating osteoarthropathy for which there is currently no effective treatment. We recently described the natural history of ochronosis in a murine model of AKU, demonstrating that deposition of ochronotic pigment begins very early in life and accumulates with age. Using this model, we were able to show that lifetime treatment with nitisinone, a potential therapy for AKU, was able to completely prevent deposition of ochronotic pigment. However, although nitisinone has been shown to inhibit ochronotic deposition, whether it can also facilitate removal of existing pigment has not yet been examined. We describe here that midlife administration of nitisinone to AKU mice arrests further deposition of ochronotic pigment in the tibiofemoral joint, but does not result in the clearance of existing pigment. We also demonstrate the dose-dependent response of plasma HGA to nitisinone, highlighting its efficacy for personalised medicine, where dosage can be tailored to the individual AKU patient.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 93%

Section: Chromatographic Conditionsmentioning

confidence: 99%

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Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice

et al. 2015

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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%

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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“…In HT-1, nitisinone prevents the formation of the highly toxic metabolites maleylacetoacetate, fumarylacetoacetate, and succinylacetone (Lindstedt et al 1992), and in combination with a tyrosine-restricted diet, it serves as a successful therapeutic intervention. In AKU, nitisinone can effectively reduce HGA and prevent ochronosis in mice (Suzuki et al Preston et al 2013) and reduce HGA in patients (Introne et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria

et al. 2015

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Background: Alkaptonuria (AKU) is a serious genetic disease due to a defect in tyrosine metabolism, leading to increased serum levels of homogentisic acid (HGA). Nitisinone decreases HGA in AKU, but the concentration-response relationship has not been previously reported.Objectives: To determine the relationship between serum concentrations of nitisinone and the effect on both HGA and tyrosine; secondly to determine steady-state pharmacokinetics of nitisinone in AKU patients.Method: Thirty-two patients with AKU received either 1, 2, 4, or 8 mg nitisinone daily. Urine and serum HGA and serum tyrosine and nitisinone were measured during 24 h at baseline (before first dose) and after 4 weeks of treatment.Results: Nitisinone pharmacokinetics (area under the curve [AUC] and maximum concentrations [C max ]) were dose proportional. The median oral clearance determined in all patients, irrespective of dose, was 3.18 mL/hÁkg (range 1.6-6.7).Nitisinone decreased urinary excretion of HGA in a concentration-dependent manner, with a maximum effect seen at average nitisinone concentrations of 3 mmol/L. The association between nitisinone and tyrosine concentrations was less pronounced. Serum levels of HGA at Week 4 were below the limit of quantitation in 65% of samples, which prevented determination of the relationship with nitisinone concentrations.Conclusion: Nitisinone exhibits dose-proportional pharmacokinetics in the studied dosage interval. Urinary excretion of HGA decreases in a concentration-dependent manner, while the increase in tyrosine is less clearly related to nitisinone concentrations.

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Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone

Cited by 90 publications

References 26 publications

Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice

Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice

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

Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria

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