Cathepsin K: Its skeletal actions and role as a therapeutic target in osteoporosis

Nature Reviews Rheumatology

Volumn 7, Issue 8, 2011, Pages 447-456

  Costa, Aline G ^a   Cusano, Natalie E ^a   Silva, Barbara C ^a   Cremers, Serge ^a   Bilezikian, John P ^a  

^a Columbia University ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AFG 495; ALENDRONIC ACID; ATORVASTATIN; BALICATIB; BISPHOSPHONIC ACID DERIVATIVE; CALCIUM; CATHEPSIN K; CATHEPSIN K INHIBITOR; COLECALCIFEROL; COLLAGEN TYPE 1; CYSTEINE PROTEINASE; CYTOCHROME P450 3A4; DENOSUMAB; ESTROGEN DERIVATIVE; IBUPROFEN; L 235; MIV 701; MIV 710; ODANACATIB; ONO 5334; PAPAIN; PARACETAMOL; PLACEBO; RELACATIB; SELECTIVE ESTROGEN RECEPTOR MODULATOR; UNCLASSIFIED DRUG; ZOLEDRONIC ACID;

BONE METASTASIS; BONE PAIN; BREAST CANCER; COLLAGEN DEGRADATION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG ERUPTION; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG METABOLISM; DRUG POTENTIATION; DRUG TARGETING; DRUG WITHDRAWAL; DYSPEPSIA; FRACTURE; HUMAN; HYPERTENSION; KNOCKOUT MOUSE; LUNG TOXICITY; MORPHEA; MULTICENTER STUDY (TOPIC); NAUSEA; NONHUMAN; OSTEOARTHRITIS; OSTEOCLAST; OSTEOLYSIS; OSTEOPOROSIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FAMILY; PRURITUS; PYCNODYSOSTOSIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SINGLE DRUG DOSE; SKIN TOXICITY; URINARY TRACT INFECTION; VOMITING;

BONE REMODELING; CATHEPSIN K; CLINICAL TRIALS, PHASE I AS TOPIC; CLINICAL TRIALS, PHASE II AS TOPIC; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; OSTEOPOROSIS;

EID: 80051471238     PISSN: 17594790     EISSN: 17594804     Source Type: Journal    
DOI: 10.1038/nrrheum.2011.77     Document Type: Review

References (97)

1. 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).
2. 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). (Pubitemid 27175344)
3. 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). (Pubitemid 26160923)
4. 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).
5. Troen, B. R. The regulation of cathepsin K gene expression. Ann. N. Y. Acad. Sci. 1068, 165-172 (2006). (Pubitemid 43824146)
6. McQueney, M. S. et al. Autocatalytic activation of human cathepsin K. J. Biol. Chem. 272, 13955-13960 (1997). (Pubitemid 27224840)
7. Rieman, D. J. et al. Biosynthesis and processing of cathepsin K in cultured human osteoclasts. Bone 28, 282-289 (2001). (Pubitemid 32192952)
8. 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).
9. 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).
10. Bühling, F. et al. Cathepsin K expression in human lung. Adv. Exp. Med. Biol. 477, 281-286 (2000). (Pubitemid 32174014)
11. Mandelin, J. et al. Human osteoblasts produce cathepsin K. Bone 38, 769-777 (2006). (Pubitemid 44498577)
12. 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). (Pubitemid 36125914)
13. Littlewood-Evans, A. J. et al. The osteoclast-Associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res. 57, 5386-5390 (1997). (Pubitemid 27516378)
14. 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). (Pubitemid 28376160)
15. 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). (Pubitemid 44833434)
16. 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). (Pubitemid 36384304)
17. 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).
18. 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).
19. 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).
20. 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). (Pubitemid 24010512)
21. 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). (Pubitemid 30056702)
22. Garnero, P. et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J. Biol. Chem. 273, 32347-32352 (1998). (Pubitemid 29177183)
23. 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). (Pubitemid 30101647)
24. 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). (Pubitemid 26160924)
25. Lecaille, F., Brömme, D. & Lalmanach, G. Biochemical properties and regulation of cathepsin K activity. Biochimie 90, 208-226 (2008). (Pubitemid 351200459)
26. 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). (Pubitemid 28211893)
27. Hou, W. S. et al. Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. Am. J. Pathol. 159, 2167-2177 (2001).
28. Dejica, V. M. et al. Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Am. J. Pathol. 173, 161-169 (2008). (Pubitemid 351947964)
29. Hou, W. S. et al. Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum. 46, 663-674 (2002).
30. Gelb, B. D., Edelson, J. G. & Desnick, R. J. Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. Nat. Genet. 10, 235-237 (1995).
31. 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).
32. Polymeropoulos, M. H. et al. The gene for pycnodysostosis maps to human chromosome 1cen-q21. Nat. Genet. 10, 238-239 (1995).
33. 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).
34. 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). (Pubitemid 46525550)
35. 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).
36. 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).
37. 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).
38. Maroteaux, P. & Lamy, M. 2 cases of a condensing osseous disease: Pynodysostosis [French]. Arch. Fr. Pediatr. 19, 267-274 (1962).
39. 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). (Pubitemid 34760024)
40. Shuler, S. E. Pycnodysostosis. Arch. Dis. Child. 38, 620-625 (1963).
41. 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). (Pubitemid 351915730)
42. Sedano, H. D., Gorlin, R. J. & Anderson, V. E. Pycnodysostosis. Clinical and genetic considerations. Am. J. Dis. Child. 116, 70-77 (1968).
43. Maroteaux, P. & Lamy, M. The malady of Toulouse-Lautrec. JAMA 191, 715-717 (1965).
44. 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). (Pubitemid 29521785)
45. 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). (Pubitemid 15102232)
46. 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). (Pubitemid 38507900)
47. 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). (Pubitemid 28522993)
48. 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). (Pubitemid 29455813)
49. Pennypacker, B. et al. Bone density, strength, and formation in adult cathepsin K (-/-) mice. Bone 44, 199-207 (2009).
50. Pennypacker, B. L. et al. Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits. J. Bone Miner. Res. 26, 252-262 (2011).
51. 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). (Pubitemid 46323177)
52. 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). (Pubitemid 40703885)
53. Fuller, K. et al. Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts. Bone 42, 200-211 (2008). (Pubitemid 350302017)
54. 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).
55. Funicello, M. et al. Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores. PLoS One 42, e683 (2007).
56. 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).
57. 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). (Pubitemid 43958494)
58. 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).
59. Hofnagel, O. & Robenek, H. Cathepsin K: Boon or bale for atherosclerotic plaque stability? Cardiovasc. Res. 81, 242-243 (2009).
60. Bühling, F. et al. Pivotal role of cathepsin K in lung fibrosis. Am. J. Pathol. 164, 2203-2216 (2004). (Pubitemid 38669366)
61. 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).
62. Yamashita, D. S. & Dodds, R. A. Cathepsin K and the design of inhibitors of cathepsin K. Curr. Pharm. Des. 6, 1-24 (2000). (Pubitemid 30395459)
63. Podgorski, I. Future of anticathepsin K drugs: Dual therapy for skeletal disease and atherosclerosis? Future Med. Chem. 1, 21-34 (2009).
64. Stoch, S. A. & Wagner, J. A. Cathepsin K inhibitors: A novel target for osteoporosis therapy. Clin. Pharmacol. Ther. 83, 172-176 (2008).
65. 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).
66. 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). (Pubitemid 44839339)
67. Le Gall, C. et al. A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res. 67, 9894-9902 (2007). (Pubitemid 47621238)
68. 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).
69. 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).
70. 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.
71. 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). (Pubitemid 43376505)
72. Lin, J. H. Bisphosphonates: A review of their pharmacokinetic properties. Bone 18, 75-85 (1996). (Pubitemid 26092586)
73. Cremers, S. & Papapoulos, S. Pharmacology of bisphosphonates. Bone doi:10.1016/j.bone.2011.01.014.
74. 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). (Pubitemid 40994085)
75. 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).
76. 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).
77. 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). (Pubitemid 351179363)
78. Isabel, E. et al. The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 20, 887-892 (2010).
79. 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).
80. 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).
81. 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).
82. Black, W. C. Peptidomimetic inhibitors of cathepsin K. Curr. Top. Med. Chem. 10, 745-751 (2010).
83. 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).
84. 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).
85. Desmarais, S. et al. Effect of cathepsin k inhibitor basicity on in vivo off-Target activities. Mol. Pharmacol. 73, 147-156 (2008). (Pubitemid 350294206)
86. 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.
87. 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).
88. 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).
89. 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). (Pubitemid 38543667)
90. 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). (Pubitemid 34270498)
91. 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).
92. 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).
93. Bauer, D. C. Discontinuation of odanacatib and other osteoporosis treatments: Here today and gone tomorrow? J. Bone Miner. Res. 26, 239-241 (2011).
94. US National Library of Medicine. ClinicalTrials.gov [online]. http://clinicaltrials.gov/ct2/show/NCT00729183 (2011).
95. US National Library of Medicine. ClinicalTrials.gov [online]. http://clinicaltrials.gov/ct2/show/NCT00529373 (2011).
96. US National Library of Medicine. ClinicalTrials.gov [online]. http://clinicaltrials.gov/ct2/show/NCT01120600 (2011).
97. 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).