Browsing by Author "Abubacker, Saleem"

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    Molecular Basis of Articular Cartilage Boundary Lubrication: Role of PRG4 Structure & Multimerisation
    (2015-06-15) Abubacker, Saleem; Schmidt, Tannin A; Matyas, John R.
    Proteoglycan 4 (PRG4) is a mucin-like glycoprotein found in synovial fluid (SF) and at the articular cartilage surface, where it is required for joint lubrication and health. Hyaluronan (HA), a glycosaminoglycan polymer, is another SF constituent that contributes to SF’s viscosity and cartilage lubrication properties. PRG4 and HA function effectively as friction reducing boundary lubricants at a cartilage-cartilage interface, though both have been studied at other interfaces with varying results. PRG4 can exist in SF as disulfide-bonded multimers, a structurally determinant characteristic of mucins, which may be necessary for its cartilage adsorption and boundary lubricating ability. A recently developed full-length recombinant human PRG4 (rhPRG4) has demonstrated appropriate higher order structure, O-linked glycosylations, and boundary lubricating ability at the ocular surface. However, it remains unclear if this rhPRG4 is able to adsorb to and function as a cartilage boundary lubricant. The objectives of this thesis were to (1) determine the effect of different sliding interface materials on the lubricating ability of PRG4 and HA by measuring the kinetic coefficient of friction, (2i) assess the cartilage adsorption and boundary lubricating ability of disulfide-bonded PRG4 multimers and PRG4 monomers, (2ii) evaluate the cartilage boundary lubricating ability of PRG4 multimers and PRG4 monomers with HA, and (3) assess the cartilage adsorption of rhPRG4 and the in vitro cartilage boundary lubricating properties of rhPRG4, with and without HA. PRG4 demonstrated boundary lubricating function at both cartilage-cartilage and cartilage-glass interfaces, while HA demonstrated friction reducing ability only at the cartilage-cartilage interface. The inter-molecular disulfide-bonded multimeric structure of PRG4 was important for its ability to adsorb to a cartilage surface and function as a boundary lubricant. Finally, rhPRG4 demonstrated cartilage adsorption and boundary lubricating function, with and without HA, equivalent to native PRG4. Collectively, these results demonstrate the effectiveness of putative cartilage boundary lubricants can be affected by the counterface, contribute to a greater understanding of the molecular basis of articular cartilage boundary lubrication of PRG4, and provide the foundation and motivation for future clinical evaluation of rhPRG4 as a biotherapeutic treatment for osteoarthritis.