Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis (original) (raw)

• Ross, P. E. in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (ed. Rosen, C. J.) 16–22 (American Society for Bone and Mineral Research, Washington, D. C., 2008).
  Book Google Scholar
• Rood, J. A., Van Horn, S., Drake, F. H., Gowen, M. & Debouck, C. Genomic organization and chromosome localization of the human cathepsin K gene (CTSK). Genomics 41, 169–176 (1997).
  Article CAS PubMed Google Scholar
• Drake, F. H. et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J. Biol. Chem. 271, 12511–12516 (1996).
  Article CAS PubMed Google Scholar
• Balkan, W. et al. Identification of NFAT binding sites that mediate stimulation of cathepsin K promoter activity by RANK ligand. Gene 446, 90–98 (2009).
  Article CAS PubMed Google Scholar
• Troen, B. R. The regulation of cathepsin K gene expression. Ann. N. Y. Acad. Sci. 1068, 165–172 (2006).
  Article CAS PubMed Google Scholar
• McQueney, M. S. et al. Autocatalytic activation of human cathepsin K. J. Biol. Chem. 272, 13955–13960 (1997).
  Article CAS PubMed Google Scholar
• Rieman, D. J. et al. Biosynthesis and processing of cathepsin K in cultured human osteoclasts. Bone 28, 282–289 (2001).
  Article CAS PubMed Google Scholar
• Inaoka, T. et al. Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochem. Biophys. Res. Commun. 206, 89–96 (1995).
  Article CAS PubMed Google Scholar
• Brömme, D. & Okamoto, K. Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. Biol. Chem. Hoppe Seyler 376, 379–384 (1995).
  Article PubMed Google Scholar
• Bühling, F. et al. Cathepsin K expression in human lung. Adv. Exp. Med. Biol. 477, 281–286 (2000).
  Article PubMed Google Scholar
• Mandelin, J. et al. Human osteoblasts produce cathepsin K. Bone 38, 769–777 (2006).
  Article CAS PubMed Google Scholar
• Brubaker, K. D., Vessella, R. L., True, L. D., Thomas, R. & Corey, E. Cathepsin K mRNA and protein expression in prostate cancer progression. J. Bone Miner. Res. 18, 222–230 (2003).
  Article CAS PubMed Google Scholar
• Littlewood-Evans, A. J. et al. The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res. 57, 5386–5390 (1997).
  CAS PubMed Google Scholar
• Sukhova, G. K., Shi, G. P., Simon, D. I., Chapman, H. A. & Libby, P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J. Clin. Invest. 102, 576–583 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Xiao, Y. et al. Cathepsin K in adipocyte differentiation and its potential role in the pathogenesis of obesity. J. Clin. Endocrinol. Metab. 91, 4520–4527 (2006).
  Article CAS PubMed Google Scholar
• Chiellini, C. et al. Identification of cathepsin K as a novel marker of adiposity in white adipose tissue. J. Cell Physiol. 195, 309–321 (2003).
  Article CAS PubMed Google Scholar
• Quintanilla-Dieck, M. J., Codriansky, K., Keady, M., Bhawan, J. & Runger, T. M. Expression and regulation of cathepsin K in skin fibroblasts. Exp. Dermatol. 18, 596–602 (2009).
  Article CAS PubMed Google Scholar
• Bou-Gharios, G. & de Crombrugghe, B. in Principles of Bone Biology (eds Bilezikian, J. P., Raisz, L. A. & Rodan, G. A.) 285–318 (Academic Press, San Diego, 2008).
  Book Google Scholar
• Cremers, S., Garnero, P. & Seibel, M. J. in Principles of Bone Biology (eds Bilezikian, J. P., Raisz, L. A. & Rodan, G. A.) 1857–1881 (Academic Press, San Diego, 2008).
  Book Google Scholar
• Rosen, H. N. et al. Specificity of urinary excretion of cross-linked N-telopeptides of type I collagen as a marker of bone turnover. Calcif. Tissue Int. 54, 26–29 (1994).
  Article CAS PubMed Google Scholar
• Rosen, H. N. et al. Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcif. Tissue Int. 66, 100–103 (2000).
  Article CAS PubMed Google Scholar
• Garnero, P. et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J. Biol. Chem. 273, 32347–32352 (1998).
  Article CAS PubMed Google Scholar
• Atley, L. M., Mort, J. S., Lalumiere, M. & Eyre, D. R. Proteolysis of human bone collagen by cathepsin K: characterization of the cleavage sites generating by cross-linked N-telopeptide neoepitope. Bone 26, 241–247 (2000).
  Article CAS PubMed Google Scholar
• Bossard, M. J. et al. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J. Biol. Chem. 271, 12517–12524 (1996).
  Article CAS PubMed Google Scholar
• Lecaille, F., Brömme, D. & Lalmanach, G. Biochemical properties and regulation of cathepsin K activity. Biochimie 90, 208–226 (2008).
  Article CAS PubMed Google Scholar
• Kafienah, W., Brömme, D., Buttle, D. J., Croucher, L. J. & Hollander, A. P. Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem. J. 331, 727–732 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Hou, W. S. et al. Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. Am. J. Pathol. 159, 2167–2177 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Dejica, V. M. et al. Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Am. J. Pathol. 173, 161–169 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Hou, W. S. et al. Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum. 46, 663–674 (2002).
  Article CAS PubMed Google Scholar
• Gelb, B. D., Edelson, J. G. & Desnick, R. J. Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. Nat. Genet. 10, 235–237 (1995).
  Article CAS PubMed Google Scholar
• Gelb, B. D., Shi, G. P., Chapman, H. A. & Desnick, R. J. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273, 1236–1238 (1996).
  Article CAS PubMed Google Scholar
• Polymeropoulos, M. H. et al. The gene for pycnodysostosis maps to human chromosome 1cen-q21. Nat. Genet. 10, 238–239 (1995).
  Article CAS PubMed Google Scholar
• Bertola, D. et al. Craniosynostosis in pycnodysostosis: broadening the spectrum of the cranial flat bone abnormalities. Am. J. Med. Genet. A 152, 2599–2603 (2010).
  Article Google Scholar
• Schilling, A. F. et al. High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. Osteoporos. Int. 18, 659–669 (2007).
  Article CAS PubMed Google Scholar
• Khan, B., Ahmed, Z. & Ahmad, W. A novel missense mutation in cathepsin K (CTSK) gene in a consanguineous Pakistani family with pycnodysostosis. J. Investig. Med. 58, 720–724 (2010).
  Article CAS PubMed Google Scholar
• Li, H. Y., Ma, H. W., Wang, H. Q. & Ma, W. H. Molecular analysis of a novel cathepsin K gene mutation in a Chinese child with pycnodysostosis. J. Int. Med. Res. 37, 264–269 (2009).
  Article CAS PubMed Google Scholar
• Hou, W. S. et al. Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis. J. Clin. Invest. 103, 731–738 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Maroteaux, P. & Lamy, M. 2 cases of a condensing osseous disease: pynodysostosis [French]. Arch. Fr. Pediatr. 19, 267–274 (1962).
  CAS PubMed Google Scholar
• Motyckova, G. & Fisher, D. E. Pycnodysostosis: role and regulation of cathepsin K in osteoclast function and human disease. Curr. Mol. Med. 2, 407–421 (2002).
  Article CAS PubMed Google Scholar
• Shuler, S. E. Pycnodysostosis. Arch. Dis. Child. 38, 620–625 (1963).
  Article CAS PubMed PubMed Central Google Scholar
• Chavassieux, P. et al. Mechanisms of the anabolic effects of teriparatide on bone: insight from the treatment of a patient with pycnodysostosis. J. Bone Miner. Res. 23, 1076–1083 (2008).
  Article CAS PubMed Google Scholar
• Sedano, H. D., Gorlin, R. J. & Anderson, V. E. Pycnodysostosis. Clinical and genetic considerations. Am. J. Dis. Child. 116, 70–77 (1968).
  Article CAS PubMed Google Scholar
• Maroteaux, P. & Lamy, M. The malady of Toulouse-Lautrec. JAMA 191, 715–717 (1965).
  Article CAS PubMed Google Scholar
• Nishi, Y. et al. Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation. J. Bone Miner. Res. 14, 1902–1908 (1999).
  Article CAS PubMed Google Scholar
• Everts, V., Aronson, D. C. & Beertsen, W. Phagocytosis of bone collagen by osteoclasts in two cases of pycnodysostosis. Calcif. Tissue Int. 37, 25–31 (1985).
  Article CAS PubMed Google Scholar
• Fratzl-Zelman, N. et al. Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J. Clin. Endocrinol. Metab. 89, 1538–1547 (2004).
  Article CAS PubMed Google Scholar
• Saftig, P. et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl Acad. Sci. USA 95, 13453–13458 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Gowen, M. et al. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J. Bone Miner. Res. 14, 1654–1663 (1999).
  Article CAS PubMed Google Scholar
• Pennypacker, B. et al. Bone density, strength, and formation in adult cathepsin K (−/−) mice. Bone 44, 199–207 (2009).
  Article CAS PubMed Google Scholar
• Pennypacker, B. L. et al. Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits. J. Bone Miner. Res. 26, 252–262 (2011).
  Article CAS PubMed Google Scholar
• Chen, W. et al. Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence. Hum. Mol. Genet. 16, 410–423 (2007).
  Article CAS PubMed Google Scholar
• Yasuda, Y., Kaleta, J. & Brömme, D. The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv. Drug Deliv. Rev. 57, 973–993 (2005).
  Article CAS PubMed Google Scholar
• Fuller, K. et al. Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts. Bone 42, 200–211 (2008).
  Article CAS PubMed Google Scholar
• Yang, M. et al. Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice. Arterioscler. Thromb. Vasc. Biol. 28, 2202–2208 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Funicello, M. et al. Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores. PLoS One 42, e683 (2007).
  Article CAS Google Scholar
• Samokhin, A. O., Wong, A., Saftig, P. & Brömme, D. Role of cathepsin K in structural changes in brachiocephalic artery during progression of atherosclerosis in apoE-deficient mice. Atherosclerosis 200, 58–68 (2008).
  Article CAS PubMed Google Scholar
• Lutgens, E. et al. Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation 113, 98–107 (2006).
  Article CAS PubMed Google Scholar
• Guo, J. et al. Leucocyte cathepsin K affects atherosclerotic lesion composition and bone mineral density in low-density lipoprotein receptor deficient mice. Cardiovasc. Res. 81, 278–285 (2009).
  Article CAS PubMed Google Scholar
• Hofnagel, O. & Robenek, H. Cathepsin K: boon or bale for atherosclerotic plaque stability? Cardiovasc. Res. 81, 242–243 (2009).
  Article CAS PubMed Google Scholar
• Bühling, F. et al. Pivotal role of cathepsin K in lung fibrosis. Am. J. Pathol. 164, 2203–2216 (2004).
  Article PubMed PubMed Central Google Scholar
• Srivastava, M. et al. Overexpression of cathepsin K in mice decreases collagen deposition and lung resistance in response to bleomycin-induced pulmonary fibrosis. Respir. Res. 9, 54 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Yamashita, D. S. & Dodds, R. A. Cathepsin K and the design of inhibitors of cathepsin K. Curr. Pharm. Des. 6, 1–24 (2000).
  Article CAS PubMed Google Scholar
• Podgorski, I. Future of anticathepsin K drugs: dual therapy for skeletal disease and atherosclerosis? Future Med. Chem. 1, 21–34 (2009).
  Article CAS PubMed Google Scholar
• Stoch, S. A. & Wagner, J. A. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin. Pharmacol. Ther. 83, 172–176 (2008).
  Article CAS PubMed Google Scholar
• Yamane, H. et al. The anabolic action of intermittent PTH in combination with cathepsin K inhibitor or alendronate differs depending on the remodeling status in bone in ovariectomized mice. Bone 44, 1055–1062 (2009).
  Article CAS PubMed Google Scholar
• Kumar, S. et al. A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone 40, 122–131 (2007).
  Article CAS PubMed Google Scholar
• Le Gall, C. et al. A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res. 67, 9894–9902 (2007).
  Article CAS PubMed Google Scholar
• McDougall, J. J., Schuelert, N. & Bowyer, J. Cathepsin K inhibition reduces CTXII levels and joint pain in the guinea pig model of spontaneous osteoarthritis. Osteoarthritis Cartilage 18, 1355–1357 (2010).
  Article CAS PubMed Google Scholar
• Seeman, E. Advances in Therapeutics: Meeting Report from the 31st Annual Meeting of the American Society for Bone and Mineral Research: September 11–15, 2009 in Denver, Colorado. IBMS BoneKEy 6, 496–502 (2009).
  Article Google Scholar
• Kassahun, K. et al. Pharmacokinetics and metabolism in rats, dogs and monkeys of the cathepsin K inhibitor odanacatib: demethylation of a methylsulfonyl moiety as a major metabolic pathway. Drug Metab. Dispos. doi:10.1124/dmd.110.037184.
• Yamashita, D. S. et al. Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors. J. Med. Chem. 49, 1597–1612 (2006).
  Article CAS PubMed Google Scholar
• Lin, J. H. Bisphosphonates: a review of their pharmacokinetic properties. Bone 18, 75–85 (1996).
  Article CAS PubMed Google Scholar
• Cremers, S. & Papapoulos, S. Pharmacology of bisphosphonates. Bone doi:10.1016/j.bone.2011.01.014.
• Cremers, S. C., Pillai, G. & Papapoulos, S. E. Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin. Pharmacokinet. 44, 551–570 (2005).
  Article CAS PubMed Google Scholar
• Body, J. J. et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin. Cancer Res. 12, 1221–1228 (2006).
  Article CAS PubMed Google Scholar
• Russell, R. G., Watts, N. B., Ebetino, F. H. & Rogers, M. J. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos. Int. 19, 733–759 (2008).
  Article CAS PubMed Google Scholar
• Gauthier, J. Y. et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 18, 923–928 (2008).
  Article CAS PubMed Google Scholar
• Isabel, E. et al. The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 20, 887–892 (2010).
  Article CAS PubMed Google Scholar
• Stoch, S. A. et al. Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo-controlled phase I studies. Clin. Pharmacol. Ther. 86, 175–182 (2009).
  Article CAS PubMed Google Scholar
• Eastell, R. et al. Safety and efficacy of the cathepsin K inhibitor, ONO-5334, in postmenopausal osteoporosis—the OCEAN study. J. Bone Miner. Res. doi:10.1002/jbmr.341 (2011).
• Adami, S. et al. Effect of one year treatment with the cathepsin-K inhibitor, balicatib, on bone mineral density (BMD) in postmenopausal women with osteopenia/osteoporosis. J. Bone Miner. Res. 21 (Suppl. 1) S24 (2006).
  Google Scholar
• Black, W. C. Peptidomimetic inhibitors of cathepsin K. Curr. Top. Med. Chem. 10, 745–751 (2010).
  Article CAS PubMed Google Scholar
• Falgueyret, J. P. et al. Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J. Med. Chem. 48, 7535–7543 (2005).
  Article CAS PubMed Google Scholar
• Peroni, A. et al. Drug-induced morphea: report of a case induced by balicatib and review of the literature. J. Am. Acad. Dermatol. 59, 125–129 (2008).
  Article PubMed Google Scholar
• Desmarais, S. et al. Effect of cathepsin k inhibitor basicity on in vivo off-target activities. Mol. Pharmacol. 73, 147–156 (2008).
  Article CAS PubMed Google Scholar
• Engelke, K. et al. Effects of the cathepsin K inhibitor, ONO-5334, on BMD as measured by 3D QCT in the hip and the spine after 12 months treatment. Presented at the 32nd Annual Meeting of the American Society for Bone and Mineral Research, Toronto, ON, Canada, October 2010.
• Bone, H. G. et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J. Bone Miner. Res. 25, 937–947 (2010).
  PubMed Google Scholar
• Eisman, J. A. et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J. Bone Miner. Res. 26, 242–251 (2011).
  Article CAS PubMed Google Scholar
• Alatalo, S. L. et al. Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers–Schonberg disease (type II autosomal dominant osteopetrosis). Clin. Chem. 50, 883–890 (2004).
  Article CAS PubMed Google Scholar
• Neele, S. J., Evertz, R., De Valk-De Roo, G., Roos, J. C. & Netelenbos, J. C. Effect of 1 year of discontinuation of raloxifene or estrogen therapy on bone mineral density after 5 years of treatment in healthy postmenopausal women. Bone 30, 599–603 (2002).
  Article CAS PubMed Google Scholar
• Bone, H. G. et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J. Clin. Endocrinol. Metab. 96, 972–980 (2011).
  Article CAS PubMed Google Scholar
• Miller, P. D. et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43, 222–229 (2008).
  Article CAS PubMed Google Scholar
• Bauer, D. C. Discontinuation of odanacatib and other osteoporosis treatments: here today and gone tomorrow? J. Bone Miner. Res. 26, 239–241 (2011).
  Article PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov[online]. (2011).
• US National Library of Medicine. ClinicalTrials.gov[online]. (2011).
• US National Library of Medicine. ClinicalTrials.gov[online]. (2011).
• Jensen, A. B. et al. The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin. Breast Cancer 10, 452–458 (2010).
  Article CAS PubMed Google Scholar