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Title: Role of osteoprotegerin and p62 in Paget's disease of bone
Author: Daroszewska, A.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2007
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Paget’s Disease of Bone (PDB) is a common condition characterised by focally increased bone turnover, which is believed to be caused by an aberrant osteoclast. Genetic factors are important in the pathogenesis of PDB and mutations in the TNFRSF11B encoding osteoprotegerin (OPG) and Sequestosome 1 (SQSTM1 ) encoding SQSTM1 or p62 cause juvenile and classic PDB of late onset respectively. OPG and p62 play an important role in the RANK-NFκB signalling pathway, key for normal osteoclastogenesis. I have shown that the TNFRSF11B G1181C polymorphism causing a lysine to asparagine change in the 3rd codon of the OPG signal peptide (SP-OPG) predisposes to PDB. Heterozygous cases for G1181C are prone to severe disease as opposed to homozygous cases (a positive heterosis effect). There is a difference in cellular localisation of respective SP-OPG variants and a degree of cellular accumulation of the SP-OPG variant containing lysine in the 3rd codon, suggesting that the latter may be inefficiently secreted at times of high demand at a local level, which could lead to increased bone resorption. Studies of p62 revealed a novel interaction between p62 and P-IκB-α and between p62 and VCP. PDB-causing mutations of the p62 UBA domain interfered with the interaction between p62 and P-IκB-α, but not between p62 and VCP, shedding a new light on the mechanism underlying the pathogenesis of PDB. Accumulation of IκB-α in the presence of the PDB-causing mutations of p62 was present, suggesting that p62 may regulate IκB-α degradation. Implications of these findings are discussed. This work provides novel insights into the molecular mechanisms underlying PDB and the findings are expected to become the groundwork for further studies trying to unravel the complexity of the pathogenesis of Paget’s disease of bone.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available