Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis

Abstract

Background Osteophyte formation is a common phenomenon in arthritis. Bone formation by endochondral ossifi cation is considered a key pathophysiological process in the formation of osteophytes. Objective 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 ossifi cation. Methods 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 specifi c 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 signalling in vivo and also signifi cantly 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. Conclusions The data indicate that blockade of hedgehog signalling by targeting Smo specifi cally inhibits osteophyte formation in arthritis without affecting infl ammation and without eliciting bone destruction at the local and systemic level. Blockade of Smo may thus be considered as a strategy to specifi cally infl uence the periosteal bone response in arthritis associated with bone apposition.

The role of hedgehog signalling in skeletal health and disease

“…[74][75][76] Blocking hedgehog signalling (by either deleting Smo in chondrocytes or by treatment with a synthetic hedgehogblocking agent) results in a substantial improvement in OA disease severity scores in mice. 74 Furthermore, blockade of the hedgehog pathway inhibits osteophyte formation in mice with arthritis induced by serum transfer, 75 and deleting IHH in chondrocytes attenuates the severity of surgi cally induced OA. 76 In addition, depletion of primary cilia in articular chondrocytes results in a shift in the predominant GLI3 activity from repressor to activator, accompanied by symptoms of early OA, in mice.…”

“…74 These Nature Reviews | Rheumatology changes, including chondrocyte hypertrophy, are similar to those observed in human OA. 74,75 Furthermore, modu lation of hedgehog signalling can attenuate the severity of traumainduced OA in mice. [74][75][76] Blocking hedgehog signalling (by either deleting Smo in chondrocytes or by treatment with a synthetic hedgehogblocking agent) results in a substantial improvement in OA disease severity scores in mice.…”

“…74,75 Furthermore, modu lation of hedgehog signalling can attenuate the severity of traumainduced OA in mice. [74][75][76] Blocking hedgehog signalling (by either deleting Smo in chondrocytes or by treatment with a synthetic hedgehogblocking agent) results in a substantial improvement in OA disease severity scores in mice. 74 Furthermore, blockade of the hedgehog pathway inhibits osteophyte formation in mice with arthritis induced by serum transfer, 75 and deleting IHH in chondrocytes attenuates the severity of surgi cally induced OA.…”

Anti-TNFα treatment decreases the previously increased serum Indian Hedgehog levels in patients with ankylosing spondylitis and affects the expression of functional Hedgehog pathway target genes

“…(8) Moreover, pharmacologic blockade of the HH pathway inhibits osteophyte formation in experimental models of inflammatory arthritis with no effect on inflammation. (9) Most recently, ectopic bone formation in the context of a rare genetic disease called progressive osseous heteroplasia, was found to depend on HH signaling and in relevant experimental models, inhibition of this pathway significantly reduced ectopic bone formation. (10) Moreover, a mouse model that was genetically manipulated in order to exhibit enhanced HH signaling in spinal chondrocytes showed spinal fusion indicating that chronic activation of the HH pathway can trigger an ankylosing phenotype.…”

Inflammation-driven bone formation in ankylosing spondylitis: characterisation of the proteoglycan-induced spondylitis mouse model

“…Filling the sub-periosteal space with osteo-or chondro-inducing biomaterials led to in situ woven bone or cartilage formation without supplementing with growth factors or additional progenitor cells [236]. Periosteal osteophyte formation is also a feature of a number of arthritic animal models, such as the AIA, CIA rat models [237], K/BxN serum transfer mouse model [238,239] and the DBA mouse model of SpA [240]. Mineralisation assessed through CT images suggests the presence of mineralised cartilage.…”