Chondroptosis in Alkaptonuric Cartilage

Abstract

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.

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

“…Common situations involve chondrocyte apoptosis, such as the terminal differentiation of hypertrophic chondrocytes from the growth plate (described in bird [85], pig [86], and rabbit [87]), as well as pathological states involving mice and rat [88] or human [89,90,91] cartilage degeneration, such as OA, or the ultra-rare alkaptonuria [92]. Histological data revealed lacunar emptying and reduced cell density within osteoarthritic cartilage, suggesting that cell death could occur during the OA process and even participate in OA onset [93].…”

“…The final stage of chondroptosis leaves the lacunae empty [25]. More recently, other studies have reported on morphological changes, similar to chondroptosis, notably after trauma-induced cell death in human and porcine discs [109], as well as in other cartilage-degeneration-linked diseases, such as the extremely rare alkaptonuria (AKU) [92]. …”

Reduced primary cilia length and altered Arl13b expression are associated with deregulated chondrocyte Hedgehog signaling in alkaptonuria

“…Moreover, significant protein oxidation and aggregation is observed in these cells which, in addition to promoting the production of ochronotic pigments, results in the altered expression of proteins involved in cell defence, protein folding, and cell organization (Braconi et al, ). In both OA and AKU tissue, chondrocytes undergo a particular form of cell death termed chondroptosis (Millucci et al, ; Perez, Luna, Rojas, & Kouri, ). Chondrocytes first appear enlarged and hypertrophic with a prominent Golgi apparatus, characterized by swollen cisternae.…”

Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease—A review

“…Model systems have been developed for investigating various effects of HGA exposure under controlled conditions in vitro and ex vivo (Figure D). in vitro models include human serum and osteoblastic (cell line) and chondrocytic (cell line and isolated from human cartilage) cell cultures . Incubation of cell cultures with HGA leads to OP formation by 4 weeks.…”