Regulation and function of mineralized tissue extra-cellular matrix proteins : studies of ADAMTS-1 and osteoadherin

Abstract: The extracellular matrix of tissues is governed and maintained by cells and a number of associated proteins. The extracellular matrix of the skeleton is highly specialized, in that it is mineralized and contains matrix-specific proteins with unique functions. Recent advances in mineralized tissue research have identified novel functions for the extracellular matrix molecules; from mere structural components to regulators of tissue maintenance and endocrine homeostasis. Osteoblasts and odontoblasts, the mineral matrix-forming cells of the skeleton and teeth, differentiate from mesenchyme progenitors. In signaling of differentiation into mature cells, the main switch towards osteoblast and odontoblast differentiation and bone formation is achieved by the signaling of bone morphogenetic proteins. Inhibitory or stimulatory signaling by several factors result in the expression of proteins and factors which are necessary for the progression towards the mature cellular phenotype. Mature mineralized tissue producing cells secrete the collagen matrix which later becomes mineralized by hydroxyapatite. In addition, these cells also secrete the non-collagenous proteins of the mineralized tissue matrix that become incorporated into the matrix. The function of many of these proteins has been studied extensively and an understanding of their effect on matrix and cellular maintenance is now emerging. Two proteins that are produced and secreted by osteoblasts and/or odontoblasts were investigated within the scope for this thesis: osteoadherin and ADAMTS-1. With an emphasis on regulation and function, it was possible to determine that osteoadherin is upregulated by terminally differentiated osteoblast and that osteoadherin affects cellular migration, proliferation and differentiation. The regulation of osteoadherin by neurotrophins in both osteoblasts and dental pulp cells suggests that a complex signaling network occurs during the development of tissue maturation. ADAMTS-1 is a multifunctional enzyme with disintegrin, thrombospondin and metalloproteinase domains. It was determined that ADAMTS-1 is upregulated by parathyroid hormone and associates with collagen and degrades it, and further that the catalytically active enzyme promotes cellular colonization of the 3D environment. In summary, the work presented in this thesis provides novel understandings for the role of extracellular matrix proteins in determining the behavior of mineralized tissue cells.