Homogentisic acid induces morphological and mechanical aberration of ochronotic cartilage in alkaptonuria |
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Authors: | Giulia Bernardini Gemma Leone Lia Millucci Marco Consumi Daniela Braconi Ottavia Spiga Silvia Galderisi Barbara Marzocchi Cecilia Viti Giovanna Giorgetti Pietro Lupetti Agnese Magnani Annalisa Santucci |
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Institution: | 1. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy;2. Dipartimento di Scienze Fisiche, della Terra e dell'Ambiente, Università degli Studi di Siena, Siena, Italy;3. Dipartimento di Scienze della Vita, Università degli Studi di Siena, Siena, Italy |
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Abstract: | 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 proteoglycans. A drastic increase in stiffness and decrease in dissipative and lubricant role ensued in AKU cartilage. Multiphoton and scanning electron microscopies revealed destruction of cell–matrix microstructure and disruption of the superficial layer. Such observations on AKU specimens were confirmed in HGA-treated healthy cartilage, indicating that HGA is the toxic responsible of morphological and mechanical alterations of cartilage in AKU. |
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Keywords: | alkaptonuria glycosaminoglycan heat capacity mesoporosity ochronosis rheology |
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