Recent drug discovery has been driven largely by a genomics-based approach. This revolution in pharmaceutics is based on localized expression of either a novel gene or homologue of a known gene found in cDNA libraries made from normal versus diseased tissue. The choice and quality of cDNA library is critical for the success of this approach. Expression is normally verified at the cellular level by either immunocytochemistry or in situ hybridization. Activity of the recombinant protein in secondary cell-based assays allows highthroughput screens to be formulated to identify small-molecule effectors of this protein. More recently, a proteomics approach has also been incorporated into this process. This technology directly measures proteins whose expression is localized in disease tissue as the basis for cell-based screens to look for either activators or inhibitors, of this activity. The majority of screens are designed to look for inhibitors. Activity of small-molecules found by screening gives rise to pharmacokinetic studies and verification of activity in animal models of the disease. Structure-activity relationship (SAR) optimization of these small-molecules allows for suitable oral bioavailability and pharmacokinetics, resulting in compounds progressing from discovery to development. Based on these strategies, we have developed inhibitors of osteoclast-mediated bone resorption and are currently screening for bone anabolic agents. In addition, we have also developed small-molecule caspase inhibitors which prevent chondrocyte apoptosis and retain cell function in an attempt to find therapeutic agents to either prevent or treat osteoarthritis. These agents may well have utility in the treatment of temporomandibular joint diseases.

Blanco, F.J., R.L. Ochs, H. Schwarz, M. Lotz (1995) Chondrocyte apoptosis induced by nitric oxide. Am J Pathol 146: 75–85.
Drake, F.H., R.A. Dodds, I.E. James, J.R. Connor, C. Debouck, S. Richardson, E. Lee-Rykaczewski, L. Coleman, D. Rieman, R. Barthlow, G. Hastings, M. Gowen (1996) Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem 271: 12511–12516.
Ellis, H.M., H.R. Horvitz (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44: 817–829.
El-Meanawy, M.A., J.R. Schelling, F. Pozuelo, M.M. Churpek, E.K. Ficker, S. Iyengar, J.R. Sedor (2000) Use of serial analysis of gene expression to generate kidney expression libraries. Am J Physiol 279: 383–392.
Gordon, E.M., R.W. Barrett, W.J. Dower, S.P.A. Fodor, M.A. Gallop (1994) Applications of combinatorial technologies to drug discovery: Combinatorial organic synthesis, library screening strategies and future directions. J Med Chem 37: 1385–1401.
Hashimoto, S., R.L. Ochs, S. Komiya, M. Lotz (1998) Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. Arthritis Rheum 41: 1632–1638.
Kouri, J.B., J.L. Rosales-Encina, P.P. Chaudhuri, J. Luna, R. Mena (1997) Apoptosis in human osteoarthritic cartilage: A microscopy report. Med Sci Res 25: 245–248.
Lander, E.S. (1996) The new genomics: Global views of biology. Science 274: 536–539.
Lee, D., S.A. Long, J.L. Adams, G. Chan, K.S. Vaidya, T.A. Francis, K. Kikly, J.D. Winkler, C.-M. Sung, C. Debouck, S. Richardson, M.A. Levy, W.E. De Wolf, Jr., P.M. Keller, T. Tomaszek, M.S. Head, M.D. Ryan, R.C. Haltiwanger, P.-H. Liang, C.A. Janson, P.J. McDevitt, K. Johanson, N.O. Concha, W. Chan, S.S. Abdel-Meguid, A.M. Badger, M.W. Lark, D.P. Nadeau, L.J. Suva, M. Gowen, M.E. Nuttall (2000) Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality. J Biol Chem 270: 16007–16014.
Mankin, H., H. Dorfman, L. Lippiello, A. Zarins (1971) Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips: Correlation of morphology and metabolic data. J Bone Joint Surg 53: 523–537.
Nuttall, M.E., D.P. Nadeau, P.W. Fisher, F. Wang, P.M. Keller, W.E. De Wolf, M.B. Goldring, D. Lee, M.A. Levy, M. Gowen, M.W. Lark (2000) Inhibition of caspase-3-like activity prevents apoptosis while retaining functionality of human chondrocytes in vitro. J Orthop Res 18: 356–363.
Pandey, A., M. Mann (2000) Proteomics to study genes and genomes. Nature 405: 837–846.
Rogge L., E. Bianchi, M. Biffi, E. Bono, S.Y.P. Chang, H. Alexander, C. Santini, G. Ferrari, L. Sinigaglia, M. Seiler, M. Neeb, J. Mous, F. Sinigaglia, U. Certa (2000) Transcript imaging of the development of human T helper cells using oligonucleotide arrays. Nat Genet 25: 96–101.
Tollet-Egnell, P., A. Flores-Morales, J. Odeberg, J. Lundeberg, G. Norstedt (2000) Differential cloning of growth hormone-regulated hepatic transcripts in the aged rat. Endocrinology 141: 910–921.
Wang, F.-L., J.C. Connor, R.A. Dodds, I.E. James, S. Kumar, M.W. Lark, M. Gowen, M.E. Nuttall (2000) Differential expression of Egr-1 in osteoarthritic compared to normal adult human articular cartilage. Osteoarthritis Cartilage 8: 161–169.
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