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Title: Expression and function of integrin-associated proteins in human articular cartilage
Author: Orazizadeh, Mahmoud
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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Both normal and OA human articular cartilage use α5β1 integrin as a mechanoreceptor, however, the molecular mechanism of integrin-mediated mechanotransduction events remains obscure. This thesis focuses on the potential roles of integrin-associated molecules, CD98 , CD47/IAP and their ligands, galectin-3, CD147, signal regulatory protein-α (SIRPα) and thrombospondin-1 (TSP1) in α5β1 integrin dependent chondrocyte mechanotransduction. CD47, CD98 and galectin 3 are shown to be expressed by chondrocytes in both normal and OA cartilage. Using the changes in membrane potential as an indicator of chondrocyte response to mechanical stimulation initial investigations showed CD98 had no identifiable role in chondrocyte mechanotransduction, whereas CD47 and its ligands, TSP1 and SIRPα, showed critical functions. Antibodies to CD47, TSP1 and SIRPα completely inhibited the electrophysiological response of normal and OA chondrocytes to 0.33 Hz cyclical mechanical stimulation. Further examination of potential roles of CD47 showed that both normal and OA chondrocytes expressed CD47 and its ligands in a similar pattern. In resting chondrocytes, CD47 was coimmunoprecipitated with α5 integrin and TSP1 but not with β1 integrin and SIRPα. Following 1minute mechanical stimulation, chondrocytes showed increased tyrosine phosphorylation of three major proteins of 125, 90 and 65 kD. This tyrosine phosphorylation was inhibited by anti-CD47. PKCα translocation from cytosolic compartment to particulate compartment following 30 seconds mechanical stimulation, in the presence of anti-CD47 was also completely inhibited. Interactions between CD47, α5 integrin and TSP1 appears to be important in the regulation of the chondrocyte responses to mechanical stimulation, regulating down stream signalling events such as tyrosine phosphorylation and PKCα translocation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available