Homogentisate 1, 2 dioxygenase is expressed in human osteoarticular cells: Implications in alkaptonuria (original) (raw)
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Journal of Cellular Physiology, 2018
Alkaptonuria (AKU) is a disease caused by a deficient homogentisate 1,2‐dioxygenase activity leading to systemic accumulation of homogentisic acid (HGA), that forms a melanin‐like polymer that progressively deposits onto connective tissues causing a pigmentation called “ochronosis” and tissue degeneration. The effects of AKU and ochronotic pigment on the biomechanical properties of articular cartilage need further investigation. To this aim, AKU cartilage was studied using thermal (thermogravimetry and differential scanning calorimetry) and rheological analysis. We found that AKU cartilage had a doubled mesopore radius compared to healthy cartilage. Since the mesoporous structure is the main responsible for maintaining a correct hydrostatic pressure and tissue homoeostasis, drastic changes of thermal and rheological parameters were found in AKU. In particular, AKU tissue lost its capability to enhance chondrocytes metabolism (decreased heat capacity) and hence the production of prot...
Alkaptonuria (AKU) is a rare disease characterized by high levels of homogentisic acid (HGA). Although HGA is excreted substantially via urine, AKU patients often suffer from ochronosis, a dark brown pigmentation of joint cartilage, heart valves, and spinal discs, leading subsequently to severe, early osteoarthropathy. A molecular mechanism linking elevated HGA to ochronosis has not yet been found; the chemical identity of the pigment is still not known, nor the mechanism by which pigmentation induces degradation in the physico-mechanical properties of joint cartilage. Here we give key insight on HGA-derived pigment composition and collagen disruption in AKU cartilage. Synthetically derived pigment and pigmented human cartilage tissue both showed hydroquinone-resembling NMR signals, but the previously hypothesized benzoquinone functionality is not observed. EPR spectroscopy showed a radical species in the synthetically derived pigment. Moreover, we observed disruption of collagen tr...
Ochronosis – a rare metabolic disease
Romanian Journal of Rheumatology
Alkaptonuria is a rare disorder, an autosomal recessive condition with genetic determinism and hereditary transmission, having a prevalence of 1 per 1 million population in USA. The pathogenesis includes the deficiency of the homogentisate 1,2-dioxygenase (HGD) enzyme, an intermediary enzyme in phenylalanine and tyrosine catabolism. Mutations in HGD gene leads to deficient levels of functional HGD and an excess of homogentisic acid (HGA). Although HGA is rapidly excreted by the kidneys, it slowly accumulates in various tissues. Due to HGA oxidase deficiency, HGA turns into melanin-like pigment which determines: alkaptonuria, accumulation in the connective tissues, in the joints, or can make cardiovascular and genitourinary deposits. The chronic accumulation of HGA destroys the affected tissue, leading to the characteristic black-blue color and to clinical symptoms of alkaptonuria. The aim of this paper is to investigate the particularities of rheumatic manifestations in a rare metab...