Smoothened‐antagonists reverse homogentisic acid‐induced alterations of Hedgehog signaling and primary cilium length in alkaptonuria. Issue 11 (29th March 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of cellular physiology. Volume 232:Issue 11(2017:Nov.)
• Page Start: 3103
• Page End: 3111
• Publication Date: 2017-03-29
• Subjects: acetylated α‐tubulin -- chondrocytes -- confocal microscopy -- ochronosis; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.25761
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract : 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. Abstract : Primary cilia of alkaptonuric (AKU) chondrocytes are shorter as compared to healthy cells and HGA treatment leads to the same phenotype. Primary cilia alterations are correlated to an aberrant Hedgehog (Hh) signaling activation. Treatment of HGA‐treated chondrocytes with antagonists of Smoothened reported cilia lengths and Hh activation to the normal levels.