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Blockade of the Hedgehog Pathway inhibits Osteophyte Formation in Arthritis

Ruiz-Heiland, Gisela and Horn, Angelika and Zerr, Pawel and Hofstetter, Willy and Baum, Wolfgang and Stock, Michael and Distler, Jörg H and Nimmerjahn, Falk and Schett, Georg and Zwerina, Jochen (2012) Blockade of the Hedgehog Pathway inhibits Osteophyte Formation in Arthritis. Annals of Rheumatic Diseases, 71 (2). pp. 400-407. ISSN 0003-4967

Abstract

Introduction: Osteophyte formation is a common phenomenon in joint disease. Bone formation by endochondral ossification is considered being a key pathophysiologic process to form osteophytes. We hypothesized that inhibition of Smoothened (Smo), a key component of the hedgehog pathway inhibits osteophyte formation as the hedgehog pathway mediates endochondral ossification.
Methods: We induced arthritis in 8 weeks old BLC6 mice by serum transfer (KxBN model). Mice were then treated by daily administration of either vehicle or LDE 223, a specific small molecule inhibitor for Smo, over 2 weeks starting at the onset of disease. Clinical course of arthritis, histological and molecular changes of bone in the affected joints as well as systemic bone changes were assessed.
Results: Serum transfer induced arthritis led to severe osteophyte formation within 2 weeks of onset. Blockade of Smo inhibited hedgehog signaling in vivo and also significantly inhibited osteophyte formation, whereas the clinical and histopathologic signs of arthritis were not affected. Also, systemic bone mass did not change. Smo inhibitor particularly blocked the formation of hypertrophic chondrocytes and collagen type X expression.
Conclusions: Our data indicate that blockade of hedgehog signaling by targeting Smo specifically inhibits osteophyte formation in arthritis without affecting inflammation and without eliciting bone destruction at the local and systemic level. Blockade of SMO may thus be considered as a strategy to specifically influence periosteal bone response in arthritis associated with bone apposition.

Item Type: Article
Additional Information: Work presented to the GPT of LDE225 and representatives of ATI and MSD in Basel on January 28, 2011, by Georg Schett. THis work was done with LDE223, closely related to LDE225 with similar potency on SMO inhibition
Keywords: LDE223, Osteophytes, ankylosing spondylitis, chondrocyte hypertrophy
Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4581

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