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Approach to discovering novel therapeutic agents for osteoporosis based on integrin receptor blockade (1995)

Chorev, Michael ; Dresner-Pollak, Rivka ; Eshel, Yoav ; [et al.]

New York : Wiley-Blackwell

Biopolymers 37 (1995), S. 367-375

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ISSN: 0006-3525

Keywords: Chemistry ; Polymer and Materials Science

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: On a global scale, osteoporosis is a major and growing public health problem. In the United States, osteoporosis is present in 24 million people (mostly women) and contributes to more than 1.3 million fractures/year. Serious morbidity and mortality result from these fractures. Current therapies for osteoporosis are few, efficacy is limited, and side effects problematic. Fundamental to the pathophysiology of osteoporosis is an imbalance between the tightly coupled processes of bone resorption and bone formation that characterize normal bone remodeling. Our laboratory is engaged in a research effort focused on elucidating the role of the osteoclast integrin in bone resorption, defining the nature of ligand-integrin interactions, and developing antagonists for cell surface adhesion molecules, particularly the αν, β3 vitronectin-like integrin receptor present on the surface of human osteoclasts. Peptides containing the internal arginine-glycine-aspartic acid (RGD) motif have been shown to inhibit osteoclast-mediated bone resorption in vivo. We are now designing more potent and selective inhibitors of bone resorption as a potential new mechanism-based therapeutic approach to osteoporosis based on a novel mechanism. In an effort to rapidly identify the highest affinity ligands for the human ανβ3 integrin, we have generated combinatorial peptide libraries containing substantial structural diversity. For instance, based on all possible sequence combinations of extracellular matrix proteins known to bind ανβ3, we recently synthesized and chemically analyzed a library of 360,000 peptides, all of which contain RGD. Human ανβ3 receptors are now available in a clonal cell line that expresses high levels of recombinant receptor, these cells can serve as a very important research tool in this project because of the limited number of bone-derived osteoclasts that can be harvested for experimentation. The library of peptides will be screened by “affinity selection”: the highest binding affinity peptide(s) will be isolated and microsequenced. Receptor-favored sequences will be synthesized and evaluated in a battery of in vitro and in vivo bioassays. Through these investigations, insight will be gained into the role of integrins in bone biology and patho-physiology, and new directions will be developed for the design of potent human ανβ3-selective antagonists for the treatment of osteoporosis. © 1994 John Wiley & Sons, Inc.

Additional Material: 6 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/bip.360370603

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Blockade of osteoclast-mediated bone resorption through occupancy of the integrin receptor: A potential approach to the therapy of osteoporosis (1994)

Dresner-Pollak, Rivka ; Rosenblatt, Michael

New York, N.Y. : Wiley-Blackwell

Journal of Cellular Biochemistry 56 (1994), S. 323-330

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ISSN: 0730-2312

Keywords: osteoclast ; bone resorption ; integrins ; RGD-containing peptides ; Life and Medical Sciences ; Cell & Developmental Biology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Biology , Chemistry and Pharmacology , Medicine

Notes: Bone resorption requires the tight attachment of the bone-resorbing cells, the osteoclasts, to the bone mineralized matric. Integrins, a class of cell surface adhesion glycoproteins, play a key role in the attachment process. Most integrins bind to their ligands via the arginyl-glycyl-aspartyl (R-G-D) tripeptide present within the ligand sequence. The interaction between integrins and ligaands results in bidirectional transfer of signals across the plasma Membrane. Tyrosine phosphorylaation occurs within cells as a result of integrin binding to ligaands and probably plays a role in the formation of the osteoclast clear zone, a specialized region of the osteoclast membraane maintained by cytoskeletal structure and involved in bone resorption.Human osteoclasts express α2β3 and αvβ3 integrins on their surface. Such signaling may also lead to “inside-out” effects, like increased expression of integrin receptors on the cell surface, or increased affinity of the integrin to its ligand. The αvβ3 integrin, a vitronectin receptor, plays an essential role in bone resorption. Antibodies to this integrin and short synthetic RGD-containing peptides are able to block bone resorption in vitro. Echistatin, an RGD-containing protein from a snake venom, binds to the αvβ3 integrin and blocks bone resssorption both in vitro and in vivo. Peptides containing the RGD motif are potential competitive “antagonists” a of the osteoclast integrins and may have utility in the blockage of bone resorption. Agonists may be identified by stimulation of intracellularsignaling. In theory, tissue spacificity can be achieved by (1) introducing specific amino acids in positions adjacent to the RGD sequence, (2) identifying non-RGD integrin binding domains, or (3) modulating the affinity of integrins for their endogenous ligands.

Additional Material: 4 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/jcb.240560308

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