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Lab Research Focus: Proteoglycans in Cartilage and the Artery Wall
The primary focus of my research concerns the structure and function of connective tissue proteoglycans (PGs). These are complex polyanionic molecules of very large size, commonly of about 106 Da. Although ubiquitous in connective tissues, they are found in highest concentration in cartilage. It is the cartilage PGs which we and others have studied most fully. Much of the water in cartilage is immobilized by interactions with PGs, and it is this bound water which is primarily responsible for the reversibly compressive properties of articular cartilages--allowing them to withstand high compressive loads without damage.
An indication of the importance of PGs is seen when they are progressively lost from human articular cartilage and arthritic conditions ensue. PGs, according to their form, serve many other functions too. Thus, relatively small keratan sulfate and dermatan sulfate PGs interact at specific sites with connective tissue collagens and are suspected of limiting fibrillogenesis. PGs exercise some control over extracellular matrix permeability, thereby influencing passage of solutes to and from cells. Highly hydrated hyaluronan provides passages through extracellular matrices for the migration of cells, especially in fetal tissues.
A proteoglycan possesses a core of protein to which a few or many glycosaminoglycan (GAG) chains are attached. Recently, sequencing of the corresponding cDNAs has given the primary structures of many PG protein cores. But, to locate sites of GAG attachment and other post-translationally modified residues (e.g., disulfide bonds) along the cores, it is also necessary to apply peptide sequencing methodologies. In doing this, we have provided a firm basis for further studies of cartilage PG interactions.
Monoclonal antibodies (MAbs) to specific PG features would be valuable for probing the structure and function of such complex macromolecules. We have raised and characterized a collection of MAbs to cartilage components. For example, our MAbs have helped us in studies of the structure and distribution of the PG-associated link proteins. Perhaps, more importantly, some MAbs recognize epitopes within GAG chains and are used for the immunohistological localization of PGs bearing specific GAGs.
A 148 kDa cartilage matrix protein (CMP) which associates with the large cartilage PG called aggrecan and type II collagen, has been found to drastically increase in amount and insolubility in cartilage with age. To study the basis for the latter phenomenon, we are raising and characterizing CMP-specific MAbs and developing a 3-dimensional chondrocyte culture system in which CMP is deposited within an extracellular matrix. Also, the appearance of autoantibodies to CMP in the circulation of patients with certain arthritic conditions is under investigation.
John R. Baker (B. 1934), Professor of Biochemistry and Molecular Genetics, received his Ph.D. degree in physiological chemistry from the University of Reading, England, in 1959. He was appointed Lecturer in Biochemistry at Trinity College, University of Dublin in 1963 after postdoctoral studies at the University of California at Davis. Dr. Baker moved to Birmingham in 1972. His research is supported through grants from the National Institute for Aging.