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Smoothened‐antagonists reverse homogentisic acid‐induced alterations of Hedgehog signaling and primary cilium length in alkaptonuria
Author(s) -
Gambassi Silvia,
Geminiani Michela,
Thorpe Stephen D.,
Bernardini Giulia,
Millucci Lia,
Braconi Daniela,
Orlandini Maurizio,
Thompson Clare L.,
Petricci Elena,
Manetti Fabrizio,
Taddei Maurizio,
Knight Martin M.,
Santucci Annalisa
Publication year - 2017
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.25761
Subject(s) - homogentisic acid , smoothened , cilium , hedgehog signaling pathway , alkaptonuria , hedgehog , indian hedgehog , microbiology and biotechnology , cartilage , chemistry , biology , signal transduction , biochemistry , anatomy
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 mechanosignaling and Hedgehog signaling pathways. Hedgehog signaling 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 signaling may also be altered in AKU. Thus, we characterized 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 signaling 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.