Inappropriate enhancement and diminution in the activity of bone resorbing cells are important causal factors in the pathophysiology of most metabolic diseases of bone. For example, osteopenia and osteopetrosis are, respectively, associated with increased or decreased levels of bone matrix degradation. It follows, therefore, that the establishment of rational therapies for the treatment of these disorders will depend upon developing a fuller understanding of the resorption mechanism. Bone resorption is a complex, multistage process initiated by the attachment of resorptive cells (or their immediate precursors) to the bone matrix. Previous studies of the latter phenomenon have revealed that: a) attachment and resorption are properties of relatively well differentiated cells; b) resorptive efficiency is paralleled by cell-bone binding; c) carbohydrates (oligosaccharides) on both cells and bone matrix are essential for attachment; d) glucocorticoids stimulate resorption by macrophages (and, perhaps, related cell types) by increasing binding efficiency; e) glucocorticoids increase binding by altering the exposure of specific membrane sugars. We now seem to be in particularly favorable position to extend our understanding of attachment/resorption mechanisms. The essential experimental techniques are largely in hand, at least one major component of the attachment mechanism has been identified (cell membrane sugars), and chemical agents (glucocorticoids) have been assessed which specifically modify both cell-bone binding and the cell membrane. Given this base, we propose to: 1) determine if osteoclasts and macrophage polykaryons attach to bone by the same mechanisms as macrophages; 2) isolate and identify the """"""""core"""""""" protein(s) of bone """"""""attachment"""""""" glycoproteins; 3) characterize the oligosaccharides associated with such glycoproteins; 4) establish the mechanisms by which glucocorticoids modulate binding and, in particular, the molecules associated with attachment; and 5) determine whether changes in membrane lipid composition and fluidity play a major role in glucocorticoid-stimulated cell-bone binding.
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