Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nurnberg, Erlangen, Germany.
Ann Rheum Dis. 2012 Mar;71(3):400-7. doi: 10.1136/ard.2010.148262. Epub 2012 Jan 10.
Osteophyte formation is a common phenomenon in arthritis. Bone formation by endochondral ossification is considered a key pathophysiological process in the formation of osteophytes.
To examine the hypothesis that inhibition of smoothened (Smo), a key component of the hedgehog pathway inhibits osteophyte formation as the hedgehog pathway mediates endochondral ossification.
Arthritis was induced in 8-week-old C57/BL6 mice by serum transfer (K/BxN model). Mice were then treated by daily administration of either vehicle or LDE223, 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.
Serum transfer-induced arthritis led to severe osteophyte formation within 2 weeks of onset. Blockade of Smo inhibited hedgehog signalling in vivo and also significantly inhibited osteophyte formation, whereas the clinical and histopathological 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.
The data indicate that blockade of hedgehog signalling 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 the periosteal bone response in arthritis associated with bone apposition.
骨赘形成是关节炎的一种常见现象。软骨内骨形成被认为是骨赘形成的关键病理生理过程。
研究抑制 smoothened（Smo），即 hedgehog 通路的关键组成部分，是否能抑制骨赘形成，因为 hedgehog 通路介导软骨内骨形成。
通过血清转移（K/BxN 模型）在 8 周龄 C57/BL6 小鼠中诱导关节炎。然后，在疾病开始时，通过每天给予载体或 Smo 的特异性小分子抑制剂 LDE223 来治疗小鼠，持续 2 周。评估关节炎的临床病程、受影响关节的骨组织学和分子变化以及全身骨变化。
血清转移诱导的关节炎在发病后 2 周内导致严重的骨赘形成。Smo 阻断抑制体内 hedgehog 信号通路，并显著抑制骨赘形成，而关节炎的临床和组织病理学迹象不受影响。此外，全身骨量没有变化。Smo 抑制剂特别阻断了肥大软骨细胞的形成和胶原 X 型的表达。
数据表明，通过靶向 Smo 阻断 hedgehog 信号通路特异性抑制关节炎中的骨赘形成，而不影响炎症，也不在局部和全身水平引起骨破坏。因此，阻断 Smo 可能被认为是一种专门影响关节炎相关骨附著的骨膜骨反应的策略。
