Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2021

Erindi/veggspjald / Talk/poster E75

The Role of the Extracellular Domain of SMO in Chondrocytes

Höfundar / Authors: Elín Sóley Sigurbjörnsdóttir (1), Máney Dögg Hjaltadóttir (1), Sigrún Elísa Magnúsdóttir (1), Abbi E. Smith (1), Eiríkur Steingrímsson (1) and Sara Sigurbjörnsdóttir (1)

Starfsvettvangur / Affiliations: 1. University of Iceland

Kynnir / Presenter: Sara Sigurbjörnsdóttir

The Hedgehog (HH) signaling pathway plays an important role in regulating normal growth and differentiation of chondrocytes. Cholesterol is essential for HH signaling activation, both for lipidation of the HH ligand and for activation of Smoothened (SMO), a key activator of the HH pathway. Several mutations in the extracellular cystein-rich domain (CRD) of SMO have been shown to affect its ability to bind to cholesterol resulting in reduced SMO activation and thereby inhibition of downstream HH signaling. A rare, missense variant SMOR173C, also localized within the CRD, has been linked to increased risk for hip osteoarthritis (OA), a painful disease causing physical disability. OA is a disease of the joint characterized by degradation of cartilage due to disrupted homeostasis of chondrocytes residing in articular cartilage. We hypothesize that the amino acid substitution, caused by the SMOR173C mutation, might result in misfolded cholesterol-binding pocket of SMO, potentially attenuating the signaling ability of SMO and thereby blocking HH signaling. Aberrant HH signaling, due to lack of cholesterol binding of SMO, could then affect phenotypic stability of chondrocytes in the hip joints resulting in OA. We aim to initially assess the in vitro cholesterol-binding capacities of the SMO CRD mutants and to investigate the effects they have on HH signaling in chondrocytes and subsequently study the effects the mutations have on osteoarthritis development in vivo using zebrafish.