Smoothened-Antagonists Reverse Homogentisic Acid-Induced Alterations of Hedgehog Signalling and Primary Cilium Length in Alkaptonuria.
J Cell Physiol
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Alkaptonuria (AKU) is an ultra-rare genetic disease, in which the accumulation of a toxic metabolite, homogentisic acid (HGA) leads to the systemic development of ochronotic aggregates. These aggregates cause severe complications mainly at the level of joints with extensive degradation of the articular cartilage. Primary cilia have been demonstrated to play an essential role in development and the maintenance of articular cartilage homeostasis, through their involvement in mechanosignalling and Hedgehog signalling pathways. Hedgehog signalling has been demonstrated to be activated in osteoarthritis (OA) and to drive cartilage degeneration in vivo. The numerous similarities between OA and AKU suggest that primary cilia hedgehog signalling may also be altered in AKU. Thus, we characterised an AKU cellular model in which healthy chondrocytes were treated with HGA (66 µM) to replicate AKU cartilage pathology. We investigated the degree of activation of the hedgehog signalling pathway and how treatment with inhibitors of the receptor Smoothened (Smo) influenced hedgehog activation and primary cilia structure. The results obtained in this work provide a further step in the comprehension of the pathophysiological features of AKU, suggesting a potential therapeutic approach to modulate AKU cartilage degradation processes through manipulation of the hedgehog pathway. This article is protected by copyright. All rights reserved.