Homogentisic acid induces cytoskeleton and extracellular matrix alteration in alkaptonuric cartilage

Abstract

Alkaptonuria (AKU) is an ultra‐rare disease caused by the deficient activity of homogentisate 1,2‐dioxygenase enzyme, leading the accumulation of homogentisic acid (HGA) in connective tissues implicating the formation of a black pigmentation called “ochronosis.” Although AKU is a multisystemic disease, the most affected tissue is the articular cartilage, which during the pathology appears to be highly damaged. In this study, a model of alkaptonuric chondrocytes and cartilage was realized to investigate the role of HGA in the alteration of the extracellular matrix (ECM). The AKU tissues lost its architecture composed of collagen, proteoglycans, and all the proteins that characterize the ECM. The cause of this alteration in AKU cartilage is attributed to a degeneration of the cytoskeletal network in chondrocytes caused by the accumulation of HGA. The three cytoskeletal proteins, actin, vimentin, and tubulin, were analyzed and a modification in their amount and disposition in AKU chondrocytes model was identified. Cytoskeleton is involved in many fundamental cellular processes; therefore, the aberration in this complex network is involved in the manifestation of AKU disease.

Ochronotic Chondropathy: A Case Report

“…As discussed earlier, Galderisi et al found differences in the concentrations and organization of actin, vimentin, and tubulin in HGA-exposed chondrocytes compared to controls [27]. These findings led to the proposition that these changes play a role in the impaired synthesis and excretion of ECM components observed in ochronosis [27]. Other literature has supported this hypothesis; a study examining cartilage matrix components from 0.6% of the total global population of AKU patients reported a lower turnover state, accelerated aging, greater total extractable protein, and lower levels of extractable glycosaminoglycans in AKU cartilage compared to samples from osteoarthritic and healthy (non-arthritic) patients [38].…”

“…As discussed earlier, Galderisi et al found differences in the concentrations and organization of actin, vimentin, and tubulin in HGA-exposed chondrocytes compared to controls [27]. These findings led to the proposition that these changes play a role in the impaired synthesis and excretion of ECM components observed in ochronosis [27].…”

“…A growing body of research has shed light on a variety of biochemical and biomechanical changes at the level of individual chondrocytes in the setting of HGA. In 2021, Galderisi et al published a study in which they used a model of AKU chondrocytes to examine the effects of HGA on the chondrocyte cytoskeleton and found distinct alterations in the concentration and organization of cytoskeletal proteins when compared to control chondrocytes [27]. More specifically, they found reduced concentrations of actin, vimentin, and tubulin with associated microstructural disorganization of all three in chondrocytes exposed to HGA compared to controls [27].…”