Homogentisic acid induces autophagy alterations leading to chondroptosis in human chondrocytes: Implications in Alkaptonuria

Galderisi, Silvia; Milella, Maria Serena; Rossi, Martina; Cicaloni, Vittoria; Rossi, Ranieri; Giustarini, Daniela; Spiga, Ottavia; Tinti, Laura; Salvini, Laura; Tinti, Cristina; Braconi, Daniela; Millucci, Lia; Lupetti, Pietro; Prischi, Filippo; Bernardini, Giulia; Santucci, Annalisa

doi:10.1016/j.abb.2022.109137

Cited by 6 publications

(4 citation statements)

References 76 publications

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Section: Cellular-level Changes In Chondrocytesmentioning

confidence: 82%

“…Another recent report showed that human chondrocytes exposed to chronic treatment of HGA experienced decreased levels of autophagic processes and the accumulation of ochronotic pigmentation, leading to the proposition that the former is responsible for the latter [31]. Chondroptosis, a distinct form of cell death of chondrocytes that has been implicated in the settings of osteoarthritis, trauma, and hyperthermia [32][33][34], was also observed in that experiment, as was mitochondrial damage [31]. Chondroptosis and classical apoptosis share a variety of similarities and differences, but one major distinction between them is the reliance on autophagocytosis in chondroptosis, rather than heterophagocytosis by phagocytes as seen in classical apoptosis [32,33].…”

Section: Cellular-level Changes In Chondrocytesmentioning

confidence: 99%

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Ochronotic Chondropathy: A Case Report

Littman,

Pietro,

Olansen

et al. 2023

Biomedicines

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Endogenous ochronosis, also known as alkaptonuria, is a rare disease known for its bluish-black discoloration of the skin, sclerae, and pinnae, as well as urine that turns black upon standing. Though rarely fatal, joint degradation is a common sequela, and many patients require multiple large joint arthroplasties throughout their lifetime. Though many aspects of the pathophysiological mechanisms of the disease have been described, questions remain, such as how the initiation of ochronotic pigmentation is prompted and the specific circumstances that make some tissues more resistant to pigmentation-related damage than others. In this report, we present the case of an 83-year-old female previously diagnosed with alkaptonuria including high-quality arthroscopic images displaying the fraying of articular cartilage. We also offer a summary of the latest literature on the pathophysiological mechanisms of the disease, including cellular-level changes observed in ochronotic chondrocytes, biochemical and mechanical alterations to the cartilaginous extracellular matrix, and patterns of pigmentation and joint degradation observed in humans and mice models. With these, we present an overview of the mechanisms of ochronotic chondropathy and joint degradation as the processes are currently understood. While alkaptonuria itself is rare, it has been termed a “fundamental disease,” implying that its study and greater understanding have the potential to lead to insights in skeletal biology in general, as well as more common pathologies such as osteoarthritis and their potential treatment mechanisms.

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Section: Cellular-level Changes In Chondrocytesmentioning

confidence: 82%

Section: Cellular-level Changes In Chondrocytesmentioning

confidence: 99%

Ochronotic Chondropathy: A Case Report

Littman,

Pietro,

Olansen

et al. 2023

Biomedicines

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“…This result was corroborated with the proteomic analysis of chondrocytes from alkaptonuric donors, showing an aberrant abundance of proteins involved in protein fate, cell structure and organization, cell rescue, defence, and stress response [ 68 ]. These findings suggest that cells react to HGA-induced oxidation by activating pathways related to stress responses; however this activation might be insufficient to restore a normal condition, allowing propagation of oxidative damage and cell apoptosis [ 89 ].…”

Section: Molecular Insights Into Alkaptonuriamentioning

confidence: 99%

“…Hh also regulates autophagy [ 102 ], a fundamental process for the degradation of damaged organelles and proteins. It was therefore interesting to note that disrupted autophagy was found in AKU [ 89 ], possibly promoting degeneration of cartilage similar to OA, especially in load-bearing joints [ 103 ] and cell apoptosis [ 89 ]. In summary, excess HGA in AKU can create a vicious crosstalk for pigment formation, tissue disruption, and disease progression mediated by oxidative stress.…”

Section: Molecular Insights Into Alkaptonuriamentioning

confidence: 99%

Alkaptonuria: From Molecular Insights to a Dedicated Digital Platform

Milella,

Geminiani,

Trezza

et al. 2024

Cells

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Alkaptonuria (AKU) is a genetic disorder that affects connective tissues of several body compartments causing cartilage degeneration, tendon calcification, heart problems, and an invalidating, early-onset form of osteoarthritis. The molecular mechanisms underlying AKU involve homogentisic acid (HGA) accumulation in cells and tissues. HGA is highly reactive, able to modify several macromolecules, and activates different pathways, mostly involved in the onset and propagation of oxidative stress and inflammation, with consequences spreading from the microscopic to the macroscopic level leading to irreversible damage. Gaining a deeper understanding of AKU molecular mechanisms may provide novel possible therapeutical approaches to counteract disease progression. In this review, we first describe inflammation and oxidative stress in AKU and discuss similarities with other more common disorders. Then, we focus on HGA reactivity and AKU molecular mechanisms. We finally describe a multi-purpose digital platform, named ApreciseKUre, created to facilitate data collection, integration, and analysis of AKU-related data.

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Homogentisic acid metabolism inhibits papillary thyroid carcinoma proliferation through ROS and p21-induced cell cycle arrest

Xie,

Lin,

et al. 2024

Life Sciences

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Homogentisic acid induces autophagy alterations leading to chondroptosis in human chondrocytes: Implications in Alkaptonuria

Cited by 6 publications

References 76 publications

Ochronotic Chondropathy: A Case Report

Ochronotic Chondropathy: A Case Report

Alkaptonuria: From Molecular Insights to a Dedicated Digital Platform

Homogentisic acid metabolism inhibits papillary thyroid carcinoma proliferation through ROS and p21-induced cell cycle arrest

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