Hedgehog signalling in bone and osteoarthritis: the role of Smoothened and cholesterol

Abstract

Hedgehog signalling is essential for development, crucial for normal anatomical arrangement and activated during tissue damage repair. Dysregulation of hedgehog signalling is associated with cancer, developmental disorders and other diseases including osteoarthritis (OA). The hedgehog gene was first discovered in Drosophila melanogaster, and the pathway is evolutionarily conserved in most animals. Although there are several hedgehog ligands with different protein expression patterns, they share a common plasma membrane receptor, Patched1 and hedgehog signalling pathway activation is transduced through the G‐protein‐coupled receptor‐like protein Smoothened (SMO) and downstream effectors. Functional assays revealed that activation of SMO is dependent on sterol binding, and cholesterol was observed bound to SMO in crystallography experiments. In vertebrates, hedgehog signalling coordinates endochondral ossification and balances osteoblast and osteoclast activation to maintain homeostasis. A recently discovered mutation of SMO in humans (SMOR173C) is predicted to alter cholesterol binding and is associated with a higher risk of hip OA. Functional studies in mice and human tissue analysis provide evidence that hedgehog signalling is pathologically activated in chondrocytes of osteoarthritic cartilage.

CCN4/WISP1 Promotes Migration of Human Primary Osteoarthritic Chondrocytes

“…Other notable correlations were with Collagen type VI alpha 3 (COL6A3, ρ = 0.6574, P = 1.78 x 10 -5 ), a collagen exclusively found in the pericellular matrix of articular cartilage 19 and Smoothened (SMO, ρ = -0.664, P = 1.24 x 10 -5 ), a part of Hedgehog signaling which is implicated in the pathogenesis of OA. 20 Analysis for these 58 genes demonstrated enrichment for particular pathways. Most significant enrichment was the GO term "neural crest cell migration" (GO 0001755; P = 7.03 x 10 -3 ), containing Coronin-1C (CORO1C), Semaphorin-3C (SEMA3C), and SMO (Table 3).…”

Lipid Metabolism in Cartilage Development, Degeneration, and Regeneration

“…Both cholesterol and sterol can activate HH signaling and cause SMO, but sterol deficiency is sufficient to inhibit HH signaling and cholesterol is required for HH activation. Subchondral bone has been demonstrated to stimulate HH signaling in animal OA models and to decrease the course of the lesion in vivo by SMO blocking [ 117 ]. Upregulation of the enzymes human 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1) and cytochrome P450 oxidase (CYP51A1), which synthesize cholesterol in chondrocytes, increases cholesterol biosynthesis during chondrogenesis, and cholesterol synthesis can promote the formation of growth plate cartilage by protecting against apoptosis and IHH expression [ 99 , 118 ].…”

Role of the hedgehog signaling pathway in rheumatic diseases: An overview

“…Blocking cholesterol may reduce the severity of OA ( 45 ). Furthermore, activation of Smo is dependent on binding to sterols ( 46 ). Smo mutations in humans affect its binding to cholesterol and are associated with a high risk of hip OA ( 37 ).…”