{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T12:02:15Z","timestamp":1791028935842,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[1997,9,1]],"date-time":"1997-09-01T00:00:00Z","timestamp":873072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1997,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We have shown previously that cathepsin K, a recently identified member of the papain superfamily of cysteine proteases, is expressed selectively in osteoclasts and is the predominant cysteine protease in these cells. Based upon its abundant cell type-selective expression, potent endoprotease activity at low pH and cellular localization at the bone interface, cathepsin K has been proposed to play a specialized role in osteoclast-mediated bone resorption. In this study, we evaluated a series of peptide aldehydes and demonstrated that they are potent cathepsin K inhibitors. These compounds inhibited osteoclast-mediated bone resorption in fetal rat long bone (FRLB) organ cultures in vitro in a concentration-dependent manner. Selected compounds were also shown to inhibit bone resorption in a human osteoclast-mediated assay in vitro. Cbz-Leu-Leu-Leu-H (in vitro enzyme inhibition Ki,app = 1.4 nM) inhibited parathyroid hormone (PTH)-stimulated resorption in the FRLB assay with an IC-50 of 20 nM and inhibited resorption by isolated human osteoclasts cultured on bovine cortical bone slices with an IC-50 of 100 nM. In the adjuvant-arthritic (AA) rat model, in situ hybridization studies demonstrated high levels of cathepsin K expression in osteoclasts at sites of extensive bone loss in the distal tibia. Cbz-Leu-Leu-Leu-H (30 mg\/kg, intraperitoneally) significantly reduced this bone loss, as well as the associated hind paw edema. In the thyroparathyriodectomized rat model, Cbz-Leu-Leu-Leu-H inhibited the increase in blood ionized calcium induced by a 6 h infusion of PTH. These data indicate that inhibitors of cathepsin K are effective at reducing osteoclast-mediated bone resorption and may have therapeutic potential in diseases of excessive bone resorption such as rheumatoid arthritis or osteoporosis.<\/jats:p>","DOI":"10.1359\/jbmr.1997.12.9.1396","type":"journal-article","created":{"date-parts":[[2006,4,26]],"date-time":"2006-04-26T22:34:26Z","timestamp":1146090866000},"page":"1396-1406","source":"Crossref","is-referenced-by-count":162,"title":["Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo"],"prefix":"10.1093","volume":"12","author":[{"given":"Bartholomew J.","family":"Votta","sequence":"first","affiliation":[{"name":"Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Molecular Recognition, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Badger","sequence":"additional","affiliation":[{"name":"Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Bradbeer","sequence":"additional","affiliation":[{"name":"Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Dodds","sequence":"additional","affiliation":[{"name":"Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian E.","family":"James","sequence":"additional","affiliation":[{"name":"Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary J.","family":"Bossard","sequence":"additional","affiliation":[{"name":"Department of Molecular Recognition, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Carr","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice R.","family":"Connor","sequence":"additional","affiliation":[{"name":"Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thaddeus A.","family":"Tomaszek","sequence":"additional","affiliation":[{"name":"Department of Molecular Recognition, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Szewczuk","sequence":"additional","affiliation":[{"name":"Department of Molecular Recognition, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred H.","family":"Drake","sequence":"additional","affiliation":[{"name":"Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel F.","family":"Veber","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxine","family":"Gowen","sequence":"additional","affiliation":[{"name":"Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020712020813000_bib1","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1042\/bj2560433","article-title":"A comparison of four cathepsins (B, L, N and S) with collagenolytic activity from rabbit spleen","volume":"256","author":"Maciewicz","year":"1988","journal-title":"Biochem J"},{"key":"2024020712020813000_bib2","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/0006-291X(84)90560-6","article-title":"In vivo and in vitro evidence for the involvement of cysteine-proteinase in bone resorption","volume":"125","author":"Delaisse","year":"1984","journal-title":"Biochem Biophys Res Commun"},{"key":"2024020712020813000_bib3","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/jbmr.5650070411","article-title":"Human cystatin C, a cysteine proteinase inhibitor, inhibits bone resorption in vitro stimulated by parathyroid hormone and parathyroid hormone-related peptide of malignancy","volume":"7","author":"Lerner","year":"1992","journal-title":"J Bone Miner Res"},{"key":"2024020712020813000_bib4","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/8756-3282(87)90007-X","article-title":"The effects of inhibitors of cysteine-proteinases and collagenase on the resorptive activity of isolated osteoclasts","volume":"8","author":"Delaisse","year":"1987","journal-title":"Bone"},{"key":"2024020712020813000_bib5","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1002\/jcb.240560116","article-title":"Inhibition of bone resorption by selective inactivators of cysteine proteinases","volume":"56","author":"Hill","year":"1994","journal-title":"J Cell Biochem"},{"key":"2024020712020813000_bib6","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1007\/BF00298591","article-title":"An ultrastructural evaluation of the effects of cysteine-proteinase inhibitors on osteoclastic resorptive functions","volume":"56","author":"Debari","year":"1995","journal-title":"Calcif Tissue Int"},{"key":"2024020712020813000_bib7","doi-asserted-by":"crossref","first-page":"12517","DOI":"10.1074\/jbc.271.21.12517","article-title":"Proteolytic activity of human osteoclast cathepsin K: Expression, purification, activation, and substrate identification","volume":"271","author":"Bossard","year":"1996","journal-title":"J Biol Chem"},{"key":"2024020712020813000_bib8","doi-asserted-by":"crossref","first-page":"12511","DOI":"10.1074\/jbc.271.21.12511","article-title":"Cathepsin K, but not cathepsins B, L, S, is abundantly expressed in human osteoclasts","volume":"271","author":"Drake","year":"1996","journal-title":"J Biol Chem"},{"key":"2024020712020813000_bib9","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/S0021-9258(17)42227-7","article-title":"Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts","volume":"269","author":"Tezuka","year":"1994","journal-title":"J Biol Chem"},{"key":"2024020712020813000_bib10","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0014-5793(94)01349-6","article-title":"Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2","volume":"357","author":"Shi","year":"1995","journal-title":"FEBS Lett"},{"key":"2024020712020813000_bib11","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1515\/bchm3.1995.376.6.379","article-title":"Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution","volume":"376","author":"Bromme","year":"1995","journal-title":"Biol Chem Hoppe-Seyler"},{"key":"2024020712020813000_bib12","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1002\/jbmr.5650100809","article-title":"Cloning and complete coding sequence of a novel human cathepsin expressed in giant cells of osteoclastomas","volume":"10","author":"Li","year":"1995","journal-title":"J Bone Miner Res"},{"key":"2024020712020813000_bib13","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1006\/bbrc.1995.1013","article-title":"Molecular cloning of human cDNA for cathepsin K: Novel cysteine proteinase predominantly expressed in bone","volume":"206","author":"Inaoka","year":"1995","journal-title":"Biochem Biophys Res Commun"},{"key":"2024020712020813000_bib14","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1074\/jbc.271.4.2126","article-title":"Human cathepsin O2, a matrix protein-degrading cysteine protease expressed in osteoclasts: Functional expression of human cathepsin O2 in Spodoptera frugiperda and characterization of the enzyme","volume":"271","author":"Bromme","year":"1996","journal-title":"J Biol Chem"},{"key":"2024020712020813000_bib15","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1126\/science.273.5279.1236","article-title":"Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency","volume":"273","author":"Gelb","year":"1996","journal-title":"Science"},{"key":"2024020712020813000_bib16","doi-asserted-by":"crossref","first-page":"69","DOI":"10.15227\/orgsyn.067.0069","article-title":"N-tert-butoxycarbonyl-L-leucinal","volume":"67","author":"Goel","year":"1989","journal-title":"Org Synth"},{"key":"2024020712020813000_bib17","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1021\/jm00163a014","article-title":"New leupeptin analogues: Synthesis and inhibition data","volume":"33","author":"McConnell","year":"1990","journal-title":"J Med Chem"},{"key":"2024020712020813000_bib18","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nsb0297-109","article-title":"Crystal structure of human osteoclast cathepsin K complex with E-64","volume":"4","author":"Zhao","year":"1997","journal-title":"Nature Struct Biol"},{"key":"2024020712020813000_bib19","first-page":"1","article-title":"The statistical analysis of enzyme kinetic data","volume":"29","author":"Cleland","year":"1979","journal-title":"Adv Enzymol Relat Areas Mol Biol"},{"key":"2024020712020813000_bib20","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1042\/bj0550170","article-title":"The determination of enzyme inhibitor constants","volume":"55","author":"Dixon","year":"1953","journal-title":"Biochem J"},{"key":"2024020712020813000_bib21","first-page":"201","article-title":"The behavior and significance of slow-binding enzyme inhibitors","volume":"61","author":"Morrison","year":"1988","journal-title":"Adv Enzymol Relat Areas Mol Biol"},{"key":"2024020712020813000_bib22","doi-asserted-by":"crossref","first-page":"9606","DOI":"10.1016\/S0021-9258(19)50133-8","article-title":"Slow-binding inhibition of NAD+ glycohydrolase by arabino analogues of beta-NAD","volume":"267","author":"Muller-Steffner","year":"1992","journal-title":"J Biol Chem"},{"key":"2024020712020813000_bib23","doi-asserted-by":"crossref","first-page":"7608","DOI":"10.1021\/bi00485a010","article-title":"Inhibition of chymotrypsin by peptidyl trifluoromethyl ketones: determinants of slow-binding kinetics","volume":"29","author":"Brady","year":"1990","journal-title":"Biochemistry"},{"key":"2024020712020813000_bib24","first-page":"14.2.1","volume-title":"Current Protocols in Molecular Biology","author":"Zeller","year":"1990"},{"key":"2024020712020813000_bib25","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1002\/jbmr.5650101109","article-title":"Human osteoclasts, not osteoblasts, deposit osteopontin onto resorption surfaces: An in vitro and ex vivo study of remodeling bone","volume":"10","author":"Dodds","year":"1995","journal-title":"J Bone Miner Res"},{"key":"2024020712020813000_bib26","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1172\/JCI105117","article-title":"Bone resorption in tissue culture: Factors influencing the response to parathyroid hormone","volume":"44","author":"Raisz","year":"1965","journal-title":"J Clin Invest"},{"key":"2024020712020813000_bib27","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/B978-0-12-644150-5.50006-6","volume-title":"Skeletal Researcher: An experimental approach","author":"Stern","year":"1979"},{"key":"2024020712020813000_bib28","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/8756-3282(94)90277-1","article-title":"Cytokine suppressive antiinflammatory compounds inhibit bone resorption in vitro","volume":"15","author":"Votta","year":"1994","journal-title":"Bone"},{"key":"2024020712020813000_bib29","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1002\/jbmr.5650111012","article-title":"The ability of human osteoclastoma-derived stromal cells to form mineralized nodules in vitro is correlated with their ability to form bone in vivo","volume":"11","author":"James","year":"1996","journal-title":"J Bone Miner Res"},{"key":"2024020712020813000_bib30","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1002\/jbmr.5650110212","article-title":"Quantification of the collagenolytic activity of isolated osteoclasts by Enzyme-linked immunosorbent assay","volume":"11","author":"Foged","year":"1996","journal-title":"J Bone Miner Res"},{"key":"2024020712020813000_bib31","doi-asserted-by":"crossref","first-page":"5673","DOI":"10.1073\/pnas.85.15.5673","article-title":"Direct action of the parathyroid hormone-like human hypercalcemic factor on bone","volume":"85","author":"Thompson","year":"1988","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020712020813000_bib32","first-page":"S366","article-title":"Transgenic mice lacking cathepsin L activity","author":"Hart","year":"1996","journal-title":"J Bone Miner Res"},{"key":"2024020712020813000_bib33","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/BF01106087","article-title":"Sclerosing bone dysplasias\u2014A target-site approach","volume":"20","author":"Greenspan","year":"1991","journal-title":"Skeletal Radiol"},{"key":"2024020712020813000_bib34","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1097\/00003086-197101000-00035","article-title":"Tetracycline-based study of bone dynamics in pycnodysostosis","volume":"74","author":"Sarnsethsiri","year":"1971","journal-title":"Clin Orthoped Rel Res"},{"key":"2024020712020813000_bib35","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1097\/00000441-197603000-00011","article-title":"Pycnodysostosis: Some aspects concerning kinetics of calcium metabolism and bone pathology","volume":"271","author":"Cabrejas","year":"1976","journal-title":"Am J Med Sci"},{"key":"2024020712020813000_bib36","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.2106\/00004623-197860080-00023","article-title":"Pycnodysostosis: A clinical, pathological, and ultramicroscopic study of a case. J","volume":"60","author":"Meredith","year":"1978","journal-title":"Bone Joint Surg"},{"key":"2024020712020813000_bib37","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/0002-9343(66)90108-2","article-title":"Pycnodysostosis, with a familial chromosome anomaly","volume":"40","author":"Elmore","year":"1966","journal-title":"Am J Med"},{"key":"2024020712020813000_bib38","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1016\/S0021-9258(18)94215-8","article-title":"Active and inactive forms of the transition-state analog protease inhibitor leupeptin: Explanation of the observed slow binding of leupeptin to cathepsin B and papain","volume":"264","author":"Schultz","year":"1989","journal-title":"J Biol Chem"},{"key":"2024020712020813000_bib39","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1210\/endo.132.3.8440195","article-title":"Inhibition of osteoclastic bone resorption in vivo by echistatin, an \u201carginyl-glycyl-aspartyl\u201d (RGD)-containing protein","volume":"132","author":"Fisher","year":"1993","journal-title":"Endocrinology"},{"key":"2024020712020813000_bib40","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1210\/endo.137.3.8603604","article-title":"Antibody to \u03b23 integrin inhibits osteoclast-mediated bone resorption in the thyroparathyroidectomized rat","volume":"137","author":"Crippes","year":"1996","journal-title":"Endocrinology"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2Fjbmr.1997.12.9.1396","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/12\/9\/1396\/56596040\/5650120910.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/12\/9\/1396\/56596040\/5650120910.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:55:33Z","timestamp":1710341733000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/12\/9\/1396-1406\/7514205"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,9,1]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2009,12,4]]},"published-print":{"date-parts":[[1997,9,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.1997.12.9.1396","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[1997,9,1]]},"published":{"date-parts":[[1997,9,1]]}}}