Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences

Expert Opinion on Drug Discovery

Volumn 11, Issue 5, 2016, Pages 457-472

  Brömme, Dieter ^a   Panwar, Preety ^a   Turan, Serap ^b  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^b MARMARA UNIVERSITY   (Turkey)

Author keywords

Cathepsin K; cathepsin K knockout; odanacatib; osteoporosis; protease inhibitors; pycnodysostosis

Indexed keywords

CATHEPSIN K; CATHEPSIN K INHIBITOR; COLLAGEN; ODANACATIB;

BONE MATRIX; CELL VIABILITY; CLINICAL TRIAL (TOPIC); DRUG SAFETY; DRUG SELECTIVITY; FRACTURE; HUMAN; KNOCKOUT MOUSE; MOUSE MODEL; NONHUMAN; OSTEOCLAST; OSTEOLYSIS; OSTEOPOROSIS; PRIORITY JOURNAL; PYCNODYSOSTOSIS; REVIEW; SIDE EFFECT; TREATMENT OUTCOME; ANIMAL; ANTAGONISTS AND INHIBITORS; DEFICIENCY; DISEASE MODEL; MOUSE;

ANIMALS; BONE RESORPTION; CATHEPSIN K; DISEASE MODELS, ANIMAL; HUMANS; MICE; OSTEOPOROSIS; PYCNODYSOSTOSIS;

EID: 84961393679     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2016.1160884     Document Type: Review

References (177)

1. Brömme D, Lecaille F. Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert Opin Investig Drugs. 2009;18 (5):585-600. doi:10.1517/13543780902832661.
2. 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. 1995;376(6):379-384.
3. Drake FH, Dodds RA, James IE, et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem. 1996;271:12511-12516.
4. Yamashita DS, Dodds RA. Cathepsin K and the design of inhibitors of cathepsin K. Curr Pharm Des. 2000;6:1-24.
5. Costa AG, Cusano NE, Silva BC, et al. Its skeletal actions and role as a therapeutic target in osteoporosis. Nat Rev Rheumatol. 2011;7 (8):447-456. doi:10.1038/nrrheum.2011.77.
6. Chapurlat RD. Treatment of postmenopausal osteoporosis with odanacatib. Expert Opin Pharmacother. 2014;15(4):559-564. doi:10.1517/14656566.2014.881470.
7. Zerbini CA, McClung MR. Odanacatib in postmenopausal women with low bone mineral density. A review of current clinical evidence. Ther Adv Musculoskelet Dis. 2013;5(4):199-209. doi:10.1177/ 1759720X13490860.
8. Runger TM, Adami S,BenhamouCL, et al. Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib. J Am Acad Dermatol. 2012;66(3):e89e96. doi:10.1016/j.jaad.2010.11.033.
9. Merck. Merck announces data from pivotal phase 3 fracture outcomes study for odanacatib, an investigational oral, once-weekly treatment for osteoporosis. 2014. Available from: http://wwwmerck newsroomcom/news-release/research-and-development-news/ merck-announces-data-pivotal-phase-3-fracture-outcomes-st
10. Bühling F, Rocken C, Brasch F, et al. Pivotal role of cathepsin K in lung fibrosis. Am J Pathol. 2004;164(6):2203-2216. doi:10.1016/ S0002-9440(10)63777-7.
11. Hou WS, Li Z, Gordon RE, et al. Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. Am J Pathol. 2001;159(6):2167-2177. doi:10.1016/S0002-9440(10)63068-4.
12. Bühling F, Reisenauer A, Gerber A, et al. Cathepsin K - a marker of macrophage differentiation? J Pathol. 2001;195(3):375-382. doi:10.1002/path.959.
13. Bühling F, Gerber A, Häckel C, et al. Expression of cathepsin K in lung epithelial cells. Am J Respir Crit Care Med. 1999;20:612-619.
14. Uusitalo H, Hiltunen A, Soderstrom M, et al. Expression of cathepsins B, H, K, L, and S and matrix metalloproteinases 9 and 13 during chondrocyte hypertrophy and endochondral ossification in mouse fracture callus. Calcif Tissue Int. 2000;67(5):382-390.
15. Sage J, De Queral D, Leblanc-Noblesse E, et al. Differential expression of cathepsins K, S and V between young and aged caucasian women skin epidermis. Matrix Biol. 2014;33:41-46. doi:10.1016/j. matbio.2013.07.002.
16. Saftig P, Wehmeyer O, Hunziker E, et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin K-deficient mice. Proc Natl Acad Sci USA. 1998;95:13453-13458.
17. Gowen M, Lazner F, Dodds R, et al. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res. 1999;14:1654-1663. doi:10.1359/jbmr.1999.14.10.1654.
18. Kiviranta R, Morko J, Alatalo SL, et al. Impaired bone resorption in cathepsin K-deficient mice is partially compensated for by enhanced osteoclastogenesis and increased expression of other proteases via an increased rankl/opg ratio. Bone. 2005;36(1):159-172. doi:10.1016/j.bone.2004.09.020.
19. Li CY, Jepsen KJ, Majeska RJ, et al. Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass. J Bone Miner Res. 2006;21(6):865-875. doi:10.1359/jbmr.060313.
20. Chen W, Yang S, Abe Y, et al. Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence. Hum Mol Genet. 2007;16(4):410-423. doi:10.1093/hmg/dd1474.
21. Gelb BD, Shi GP, Chapman HA, et al. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996;273:1236-1238.
22. Turan S. Current research on pycnodysostosis. Intractable Rare Dis Res. 2014;3(3):91-93. doi:10.5582/irdr.2014.01014.
23. Gelb BD, Shi G-P, Heller M, et al. Structure and chromosomal assignment of the human cathepsin K gene. Genomics. 1997;41:258-262. doi:10.1006/geno.1997.4631.
24. Rantakokko J, Kiviranta R, Eerola R, et al. Complete genomic structure of the mouse cathepsin K gene (ctsk) and its localization next to the arnt gene on mouse chromosome 3. Matrix Biol. 1999;18(2):155-161.
25. Billington CJ, Mason P, Magny MC, et al. The slow-binding inhibition of cathepsin K by its propeptide. Biochem Biophys Res Commun. 2000;276(3):924-929. doi:10.1006/bbrc.2000.3553.
26. Wiederanders B, Kaulmann G, Schilling K. Functions of propeptide parts in cysteine proteases. Curr Protein Pept Sci. 2003;4(5):309-326.
27. Brömme D, Okamoto K, Wang BB, et al. 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. J Biol Chem. 1996;271(4):2126-2132.
28. Hou W-S, Li W, Keyszer G, et al. Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum. 2002;46:663-674. doi:10.1002/art.10114.
29. Runger TM, Quintanilla-Dieck MJ, Bhawan J. Role of cathepsin K in the turnover of the dermal extracellular matrix during scar formation. J Invest Dermatol. 2007;127(2):293-297. doi:10.1038/sj. jid.5700535.
30. Bühling F, Waldburg N, Krüger S, et al. Expression of cathepsins B, H, K, L and S during human fetal lung development. Dev Dyn. 2002;225(1):14-21. doi:10.1002/dvdy.10134.
31. Bühling F, Waldburg N, Reisenauer A, et al. Lysosomal cysteine proteases in the lung: role in protein processing and immunoregulation. Eur Respir J. 2004;23(4):620-628.
32. Morko JP, Soderstrom M, Saamanen AM, et al. Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis. Ann Rheum Dis. 2004;63(6):649-655. doi:10.1136/ard.2002.004671.
33. Dejica VM, Mort JS, Laverty S, et al. Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Am J Pathol. 2008;173(1):161-169. doi:10.2353/ajpath.2008.070494.
34. Sukhova GK, Shi G,P, Simon DI, et al. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998;102:576-583. doi:10.1172/JCI181.
35. Dauth S, Sirbulescu RF, Jordans S, et al. Cathepsin K deficiency in mice induces structural and metabolic changes in the central nervous system that are associated with learning and memory deficits. BMC Neurosci. 2011;12:74. doi:10.1186/1471-2202-12-74.
36. Ljusberg J, Wang Y, Lang P, et al. Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts. J Biol Chem. 2005;280(31):28370-28381. doi:10.1074/jbc.M502469200.
37. Tepel C, Brömme D, Herzog V, et al. Cathepsin K in thyroid epithelial cells: sequence, localization and possible function in extracellular proteolysis of thyroglobulin. J Cell Sci. 2000;113:4487-4498.
38. Sharma V, Panwar P, O'Donoghue AJ, et al. Structural requirements for the collagenase and elastase activity of cathepsin K and its selective inhibition by an exosite inhibitor. Biochem J. 2015;465 (1):163-173. doi:10.1042/BJ20140809.
39. Bossard MJ, Tomaszek TT, Thompson SK, et al. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem. 1996;271:12517-12524.
40. Lendeckel U, Kahne T, Ten Have S, et al. Cathepsin K generates enkephalin from beta-endorphin: a new mechanism with possible relevance for schizophrenia. Neurochem Int. 2009;54(7):410-417. doi:10.1016/j.neuint.2009.01.011.
41. Zhang D, Leung N, Weber E, et al. The effect of cathepsin K deficiency on airway development and TGF-beta1 degradation. Respir Res. 2011;12:72.
42. Fuller K, Lawrence KM, Ross JL, et al. Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts. Bone. 2008;42(1):200-211. doi:10.1016/j.bone.2007.09.044.
43. Godat E, Lecaille F, Desmazes C, et al. A cysteine protease with unique kinin-degrading properties. Biochem J. 2004;383(Pt. 3):501-506. doi:10.1042/BJ20040864.
44. Garnero P, Borel O, Byrjalsen I, et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem. 1998;273:32347-32352.
45. Kafienah W, Brömme D, Buttle DJ, et al. Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem J. 1998;331:727-732.
46. Li Z, Hou WS, Brömme D. Collagenolytic activity of cathepsin K is specifically modulated by cartilage-resident chondroitin sulfates. Biochemistry. 2000;39:529-536.
47. Li Z, Hou WS, Escalante-Torres CR, et al. Collagenase activity of cathepsin K depends on complex formation with chondroitin sulfate. J Biol Chem. 2002;277(32):28669-28676. doi:10.1074/jbc. M204004200.
48. Li Z, Kienetz M, Cherney MM, et al. The crystal and molecular structures of a cathepsin K:chondroitin sulfate complex. J Mol Biol. 2008;383(1):78-91. doi:10.1016/j.jmb.2008.07.038.
49. Aguda AH, Panwar P, Du X, et al. Structural basis of collagen fiber degradation by cathepsin K. Proc Natl Acad Sci U S A. 2014;111 (49):17474-17479. doi:10.1073/pnas.1414126111.
50. Chung L, Dinakarpandian D, Yoshida N, et al. Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysis. Embo J. 2004;23(15):3020-3030. doi:10.1038/sj. emboj.7600318.
51. Cherney MM, Lecaille F, Kienitz M, et al. Structure-activity analysis of cathepsin K/chondroitin 4-sulfate interactions. J Biol Chem. 2011;286(11):8988-8998. doi:10.1074/jbc.M110.126706.
52. Novinec M, Korenc M, Caflisch A, et al. A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods. Nat Commun. 2014;5:3287.
53. Kumar S, Dare L, Vasko-Moser JA, 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. 2007;40(1):122-131. doi:10.1016/j. bone.2006.07.015.
54. Desmarais S, Masse F, Percival MD. Pharmacological inhibitors to identify roles of cathepsin K in cell-based studies: a comparison of available tools. Biol Chem. 2009;390(9):941-948. doi:10.1515/ BC.2009.092.
55. GSK. An open-label, two-period, fixed sequence, randomized, parallel group, interaction study to determine the effects of repeat doses of relacatib on the metabolism of acetaminophen, ibuprofen and atorvastatin in healthy postmenopausal female subjects. 2009. Available from: http://wwwgsk-clinicalstudyregistercom/study/SB- 462795/008 - ps
56. Peroni A, Zini A, Braga V, et al. Drug-induced morphea: report of a case induced by balicatib and review of the literature. J Am Acad Dermatol. 2008;59(1):125-129. doi:10.1016/j.jaad.2008.03.009.
57. Falgueyret JP, Desmarais S, Oballa R, et al. Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J Med Chem. 2005;48(24):7535-7543. doi:10.1021/jm0504961.
58. Desmarais S, Black WC, Oballa R, et al. Effect of cathepsin K inhibitor basicity on in vivo off-target activities. Mol Pharmacol. 2008;73(1):147-156. doi:10.1124/mol.107.039511.
59. Chappard D, Libouban H, Mindeholm L, et al. The cathepsin K inhibitor AAE581 induces morphological changes in osteoclasts of treated patients. Microsc Res Tech. 2010;73(7):726-732. doi:10.1002/jemt.20813.
60. Everts V, Beertsen W, Tigchelaar-Gutter W. The digestion of phagocytosed collagen is inhibited by the proteinase inhibitors leupeptin and E-64. Coll Relat Res. 1985;5(4):315-336.
61. Stroup GB, Kumar S, Jerome CP. Treatment with a potent cathepsin K inhibitor preserves cortical and trabecular bone mass in ovariectomized monkeys. Calcif Tissue Int. 2009;85(4):344-355. doi:10.1007/s00223-009-9279-x.
62. Jerome C, Missbach M, Gamse R. Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys. Osteoporos Int. 2011;22(12):3001-3011. doi:10.1007/s00198-011-1529-x.
63. Holford N, Pillai G, Kaila N, et al. Pkpd model for cathepsin K inhibition with balicatib and change in bone turnover biomarkers, in particular NTx. 2006. Available from: http://wwwpage-meetin geu/pdf-assets/5245-PAGE-AAE581-TLPpdf
64. Masarachia PJ, Pennypacker BL, Pickarski M, et al. Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys. J Bone Miner Res. 2012;27(3):509-523. doi:10.1002/jbmr.1475.
65. Cusick T, Chen CM, Pennypacker BL, et al. Odanacatib treatment increases hip bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey. J Bone Miner Res. 2012;27(3):524-537. doi:10.1002/jbmr.1477.
66. Stoch SA, Zajic S, Stone J, 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. 2009;86(2):175-182. doi:10.1038/clpt.2009.60.
67. Bone HG, McClung MR, Roux C, et al. Odanacatib, a cathepsin K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res. 2010;25(5):937-947. doi:10.1359/jbmr.091035.
68. Bone HG, Dempster DW, Eisman JA, et al. Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of loft, the long-term odanacatib fracture trial. Osteoporos Int. 2015;26(2):699-712. doi:10.1007/s00198-014-2944-6.
69. Lindstrom E, Vranga L, Sediga S, et al. Effect of the selective cathepsin K inhibitor MIV-711 on bone resorption and cartilage degradation biomarkers and on knee joint pathology in dogs subjected to partial medial meniscectomy, an experimental model of osteoarthritis. Bone. 2012;50(Supplement 1):S188S189. doi:10.1016/ j.bone.2012.02.598.
70. Positive results from a phase i study with MIV-711 for the treatment of osteoarthritis and other bone related disorders. 2013 Available from: http://news.cision.com/medivir/r/positive-results-from-aphase- i-study-with-miv-711-for-the-treatment-of-osteoarthritisand- other-bon,c9479286
71. Ochi Y, Yamada H, Mori H, et al. Effects of eight-month treatment with ono-5334, a cathepsin K inhibitor, on bone metabolism, strength and microstructure in ovariectomized cynomolgus monkeys. Bone. 2014;65:1-8. doi:10.1016/j.bone.2014.04.023.
72. Nagase S, Ohyama M, Hashimoto Y, et al. Pharmacodynamic effects on biochemical markers of bone turnover and pharmacokinetics of the cathepsin K inhibitor, ONO-5334, in an ascending multipledose, phase 1 study. J Clin Pharmacol. 2012;52(3):306-318. doi:10.1177/0091270011399080.
73. Eastell R, Nagase S, Small M, et al. Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the ocean study. J Bone Miner Res. 2014;29(2):458-466. doi:10.1002/jbmr.2047.
74. Engelke K, Nagase S, Fuerst T, et al. The effect of the cathepsin K inhibitor ONO-5334 on trabecular and cortical bone in postmenopausal osteoporosis: the ocean study. J Bone Miner Res. 2014;29 (3):629-638. doi:10.1002/jbmr.2080.
75. Eastell R, Nagase S, Ohyama M, et al. Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the ocean study. J Bone Miner Res. 2011;26(6):1303-1312. doi:10.1002/jbmr.341.
76. Medivir. Medivir presented its cathepsin K program at the ongoing 31st asbmr meeting in denver, USA. 2009. Available from: http:// wwwdrugscom/clinical-trials/medivir-presented-cathepsin-k-pro gram-ongoing-31st-asbmr-meeting-denver-usa-8077html
77. Medivir. Medivir: Positive results from a phase I study with MIV-711 for the treatment of osteoarthritis and other bone related disorders. 2013. Available from: http://wwwmarketwatchcom/story/medivirpositive- results-from-a-phase-i-study-with-miv-711-for-the-treat ment-of-osteoarthritis-and-other-bone-related-disorders-2013-10-09
78. Gauthier JY, Chauret N, Cromlish W, et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008;18(3):923-928. doi:10.1016/j.bmcl.2007.12.047.
79. Chapurlat RD. Odanacatib: a review of its potential in the management of osteoporosis in postmenopausal women. Ther Adv Musculoskelet Dis. 2015;7(3):103-109. doi:10.1177/ 1759720X15580903.
80. Stoch SA, Zajic S, Stone JA, et al. Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics-results from single oral dose studies in healthy volunteers. Br J Clin Pharmacol. 2013;75(5):1240-1254. doi:10.1111/j.1365-2125.2012.04471.x.
81. Pennypacker BL, Gilberto D, Gatto NT, et al. Odanacatib increases mineralized callus during fracture healing in a rabbit ulnar osteotomy model. J Orthop Res. 2016;34(1):72-80. doi:10.1002/jor.22982.
82. Feng S, Luo Z, Liu D. Efficacy and safety of odanacatib treatment for patients with osteoporosis: a meta-analysis. J Bone Miner Metab. 2015;33(4):448-454. doi:10.1007/s00774-014-0609-3.
83. Duong LT. Therapeutic inhibition of cathepsin K-reducing bone resorption while maintaining bone formation. Bonekey Reports. 2012. Article number 67. doi:10.1038/bonekey.2012.67.
84. Fujii T, Ishikawa M, Kubo A, et al. Effect of SI-591, a new class of cathepsin K inhibitor with peptidomimetic structure, on bone metabolism in vitro and in vivo. Bone. 2015;81:427-434. doi:10.1016/j.bone.2015.08.016.
85. Eisman JA, Bone HG, Hosking DJ, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: threeyear continued therapy and resolution of effect. J Bone Miner Res. 2011;26(2):242-251. doi:10.1002/jbmr.212.
86. Bauer DC. Discontinuation of odanacatib and other osteoporosis treatments: here today and gone tomorrow? J Bone Miner Res. 2011;26(2):239-241. doi:10.1002/jbmr.335.
87. Garnero P, Ferreras M, Karsdal MA, et al. The type I collagen fragments ICTP and CTx reveal distinct enzymatic pathways of bone collagen degradation. J Bone Miner Res. 2003;18(5):859-867. doi:10.1359/jbmr.2003.18.5.859.
88. Everts V, Delaisse JM, Korper W, et al. The bone lining cell: its role in cleaning howship's lacunae and initiating bone formation. J Bone Miner Res. 2002;17(1):77-90. doi:10.1359/jbmr.2002.17.1.77.
89. Bonde M, Garnero P, Fledelius C, et al. Measurement of bone degradation products in serum using antibodies reactive with an isomerized form of an 8 amino acid sequence of the C-telopeptide of type I collagen. J Bone Miner Res. 1997;12(7):1028-1034. doi:10.1359/jbmr.1997.12.7.1028.
90. Langdahl B, Binkley N, Bone H, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study. J Bone Miner Res. 2012;27 (11):2251-2258. doi:10.1002/jbmr.1695.
91. Pennypacker B, Shea M, Liu Q, et al. Bone density, strength, and formation in adult cathepsin K (-/-) mice. Bone. 2009;44(2):199-207. doi:10.1016/j.bone.2008.08.130.
92. Kiviranta R, Morko J, Uusitalo H, et al. Accelerated turnover of metaphyseal trabecular bone in mice overexpressing cathepsin K. J Bone Miner Res. 2001;16(8):1444-1452. doi:10.1359/ jbmr.2001.16.8.1444.
93. Zenger S, Hollberg K, Ljusberg J, et al. Proteolytic processing and polarized secretion of tartrate-resistant acid phosphatase is altered in a subpopulation of metaphyseal osteoclasts in cathepsin K-deficient mice. Bone. 2007;41(5):820-832. doi:10.1016/j. bone.2007.07.010.
94. Zhuo Y, Gauthier JY, Black WC, et al. Inhibition of bone resorption by the cathepsin K inhibitor odanacatib is fully reversible. Bone. 2014;67:269-280. doi:10.1016/j.bone.2014.07.013.
95. Lotinun S, Kiviranta R, Matsubara T, et al. Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest. 2013;123(2):666-681. doi:10.1172/JCI64840.
96. Scimeca JC, Franchi A, Trojani C, et al. The gene encoding the mouse homologue of the human osteoclast-specific 116-kDa v-ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants. Bone. 2000;26(3):207-213.
97. Li YP, Chen W, Liang Y, et al. Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet. 1999;23(4):447-451. doi:10.1038/70563.
98. Thudium CS, Jensen VK, Karsdal MA, et al. Disruption of the v-ATPase functionality as a way to uncouple bone formation and resorption - a novel target for treatment of osteoporosis. Curr Protein Pept Sci. 2012;13(2):141-151.
99. Neutzsky-Wulff AV, Sims NA, Supanchart C, et al. Severe developmental bone phenotype in CLC-7 deficient mice. Dev Biol. 2010;344 (2):1001-1010. doi:10.1016/j.ydbio.2010.06.018.
100. Yuan FL, Li X, Lu WG, et al. The vacuolarATPase in bone cells: a potential therapeutic target in osteoporosis. Mol Biol Rep. 2010;37 (7):3561-3566. doi:10.1007/s11033-010-0004-7.
101. Schaller S, Henriksen K, Sorensen MG, et al. The role of chloride channels in osteoclasts: CLC-7 as a target for osteoporosis treatment. Drug News Perspect. 2005;18(8):489-495. doi:10.1358/ dnp.2005.18.8.944546.
102. Kozawa E, Nishida Y, Cheng XW, et al. Osteoarthritic change is delayed in a ctsk-knockout mouse model of osteoarthritis. Arthritis Rheum. 2012;64(2):454-464. doi:10.1002/art.33398.
103. Schurigt U, Hummel KM, Petrow PK, et al. Cathepsin K deficiency partially inhibits, but does not prevent, bone destruction in human tumor necrosis factor-transgenic mice. Arthritis Rheum. 2008;58 (2):422-434. doi:10.1002/art.23224.
104. Morko J, Kiviranta R, Joronen K, et al. Spontaneous development of synovitis and cartilage degeneration in transgenic mice overexpressing cathepsin K. Arthritis Rheum. 2005;52(12):3713-3717. doi:10.1002/art.21423.
105. Van Den Brule S, Misson P, Buhling F, et al. Overexpression of cathepsin K during silica-induced lung fibrosis and control by TGF-beta. Respir Res. 2005;6:84.
106. Zhang D, Huang C, Yang C, et al. Antifibrotic effects of curcumin are associated with overexpression of cathepsins K and L in bleomycin treated mice and human fibroblasts. Respir Res. 2011;12:154.
107. Knaapi J, Lukkarinen H, Kiviranta R, et al. Cathepsin K deficiency aggravates lung injury in hyperoxia-exposed newborn mice. Exp Lung Res. 2011;37(7):408-418. doi:10.3109/01902148.2011.581738.
108. Yang M, Sun J, Zhang T, et al. Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice. Arterioscler Thromb Vasc Biol. 2008;28(12):2202-2208. doi:10.1161/ATVBAHA.108.172320.
109. Lutgens E, Lutgens SP, Faber BC, et al. Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation. 2006;113(1):98-107. doi:10.1161/ CIRCULATIONAHA.105.561449.
110. Samokhin AO, Wong A, Saftig P, et al. Role of cathepsin K in structural changes in brachiocephalic artery during progression of atherosclerosis in apoe-deficient mice. Atherosclerosis. 2008;200 (1):58-68. doi:10.1016/j.atherosclerosis.2007.12.047.
111. Hu L, Cheng XW, Song H, et al. Cathepsin K activity controls injuryrelated vascular repair in mice. Hypertension. 2014;63(3):607-615. doi:10.1161/HYPERTENSIONAHA.113.02141.
112. Hua Y, Xu X, Shi GP, et al. Cathepsin K knockout alleviates pressure overload-induced cardiac hypertrophy. Hypertension. 2013;61 (6):1184-1192. doi:10.1161/HYPERTENSIONAHA.111.00947.
113. Hua Y, Zhang Y, Dolence J, et al. Cathepsin K knockout mitigates high-fat diet-induced cardiac hypertrophy and contractile dysfunction. Diabetes. 2013;62(2):498-509. doi:10.2337/db12-0350.
114. Bernstein HG, Bukowska A, Dobrowolny H, et al. Cathepsin K and schizophrenia. Synapse. 2007;61(4):252-253. doi:10.1002/syn.20358.
115. Podgorski I. Future of anticathepsin K drugs: dual therapy for skeletal disease and atherosclerosis? Future Med Chem. 2009;1(1):21-34.
116. Maroteaux P, Lamy M. [pyknodysostosis]. Presse Med. 1962;70:9991002.
117. Maroteaux P, Lamy M. [2 cases of a condensing osseous disease: pynodysostosis]. Arch Fr Pediatr. 1962;19:267-274.
118. Donnarumma M, Regis S, Tappino B, et al. Molecular analysis and characterization of nine novel ctsk mutations in twelve patients affected by pycnodysostosis. Mutation in brief #961. Online. Hum Mutat. 2007;28(5):524. doi:10.1002/humu.v28:5.
119. Fujita Y, Nakata K, Yasui N, et al. Novel mutations of the cathepsin K gene in patients with pycnodysostosis and their characterization. J Clin Endocrinol Metab. 2000;85:425-431. doi:10.1210/jcem.85.1.6247.
120. Xue Y, Cai T, Shi S, et al. Clinical and animal research findings in pycnodysostosis and gene mutations of cathepsin K from 1996 to 2011. Orphanet J Rare Dis. 2011;6:20. doi:10.1186/1750-1172-6-48.
121. Maroteaux P, Lamy M. The malady of Toulouse-Lautrec. J Am Med Ass. 1965;191:111-113. doi:10.1001/jama.1965.03080090029007.
122. Valdes-Flores M, Hidalgo-Bravo A, Casas-Avila L, et al. Molecular and clinical analysis in a series of patients with pycnodysostosis reveals some uncommon phenotypic findings. Int J Clin Exp Med. 2014;7(11):3915-3923.
123. Arman A, Bereket A, Coker A, et al. Cathepsin K analysis in a pycnodysostosis cohort: demographic, genotypic and phenotypic features. Orphanet J Rare Dis. 2014;9:60.
124. Kyung SE, Horton JC. Papilledema from craniosynostosis in pycnodysostosis. Pediatr Neurol. 2015;52(1):128-129. doi:10.1016/j. pediatrneurol.2014.09.021.
125. Pangrazio A, Puddu A, Oppo M, et al. Exome sequencing identifies ctsk mutations in patients originally diagnosed as intermediate osteopetrosis. Bone. 2014;59:122126.
126. Caracas HP, Figueiredo PS, Mestrinho HD, et al. Pycnodysostosis with craniosynostosis: case report of the craniofacial and oral features. Clin Dysmorphol. 2012;21(1):19-21. doi:10.1097/MCD.0b013e32834c7da7.
127. Osimani S, Husson I, Passemard S, et al. Craniosynostosis: a rare complication of pycnodysostosis. Eur J Med Genet. 2010;53(2):89-92. doi:10.1016/j.ejmg.2009.12.001.
128. Bertola D, Aguena M, Yamamoto G, et al. Obesity in pycnodysostosis due to UPD1: possible effect of an imprinted gene on chromosome 1. Am J Med Genet A. 2011;155A(6):1483-1486. doi:10.1002/ajmg. a.33989.
129. Teissier N, Jacquemont ML, Blancal JP, et al. Severe snoring in a child with pycnodysostosis treated with a bilateral rib graft. Cleft Palate Craniofac J. 2009;46(1):93-96. doi:10.1597/06-199.1.
130. S R, B PR, B S,.Prakash S, Osteomyelitis in pycnodysostosis - report of 2 clinical cases. J Clin Diagn Res. 2015;9(1):ZD15ZD17. doi:10.7860/JCDR/2015/10114.5461.
131. Landa S, Esteban S, Montes E, et al. Maxillofacial alterations in a family with pycnodysostosis. Med Oral. 2000;5(3):169-176.
132. Sedano HD, Gorlin RJ, Anderson VE. Pycnodysostosis: clinical and genetic considerations. Amer J Dis Child. 1968;116:70-77.
133. Edelson JG, Obad S, Geiger R, et al. Pycnodysostosis. Orthopedic aspects with a description of 14 new cases. Clin Orthop Relat Res. 1992;280:263-276.
134. Soliman AT, Ramadan MA, Sherif A, et al. Pycnodysostosis: clinical, radiologic, and endocrine evaluation and linear growth after growth hormone therapy. Metabolism. 2001;50(8):905-911. doi:10.1053/ meta.2001.24924.
135. Rothenbuhler A, Piquard C, Gueorguieva I, et al. Near normalization of adult height and body proportions by growth hormone in pycnodysostosis. J Clin Endocrinol Metab. 2010;95(6):2827-2831. doi:10.1210/jc.2009-2531.
136. Oksjoki S, Soderstrom M, Vuorio E, et al. Differential expression patterns of cathepsins B, H, K, L, and S in the mouse ovary. Mol Hum Reprod. 2001;7(1):27-34.
137. Anway MD, Wright WW, Zirkin BR, et al. Expression and localization of cathepsin K in adult rat sertoli cells. Biol Reprod. 2004;70(3):562-569. doi:10.1095/biolreprod.103.018291.
138. Chavassieux P, Asser Karsdal M, Segovia-Silvestre T, et al. Mechanisms of the anabolic effects of teriparatide on bone: insight from the treatment of a patient with pycnodysostosis. J Bone Miner Res. 2008;23(7):1076-1083. doi:10.1359/jbmr.080231.
139. Fratzl-Zelman N, Valenta A, Roschger P, et al. Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J Clin Endocrinol Metab. 2004;89(4):1538-1547. doi:10.1210/jc.2003-031055.
140. Nishi Y, Atley L, Eyre DE, et al. Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation. J Bone Miner Res. 1999;14(11):1902-1908. doi:10.1359/ jbmr.1999.14.11.1902.
141. Ainola M, Valleala H, Nykanen P, et al. Erosive arthritis in a patient with pycnodysostosis: an experiment of nature. Arthritis Rheum. 2008;58(11):3394-3401. doi:10.1002/art.23996.
142. Yousefzadeh DK, Agha AS, Reinertson J. Radiographic studies of upper airway obstruction with cor pulmonale in a patient with pycnodysostosis. Pediatr Radiol. 1979;8(1):45-47.
143. Aronson DC, Heymans HS, Bijlmer RP. Cor pulmonale and acute liver necrosis, due to upper airway obstruction as part of pycnodysostosis. Eur J Pediatr. 1984;141(4):251-253.
144. Kshirsagar VY, Ahmed M, Nagarsenkar S, et al. Ichthyosis vulgaris and pycnodysostosis: an unusual occurrence. Acta Med Acad. 2012;41(2):214-218. doi:10.5644/ama2006-124.54.
145. Ozdemir TR, Atik T, Karaca E, et al. A novel mutation in two families with pycnodysostosis. Clin Dysmorphol. 2013;22(3):102-105. doi:10.1097/MCD.0b013e3283619632.
146. Shuler SE. Pycnodysostosis. Arch Dis Child. 1963;38:620-625.
147. Gelb BD, Willner JP, Dunn TM, et al. Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. Am J Hum Genet. 1998;62(4):848-854. doi:10.1086/301795.
148. Lachman RS. Neurologic abnormalities in the skeletal dysplasias: a clinical and radiological perspective. Am J Med Genet. 1997;69 (1):33-43.
149. Singh A, Cuevas-Covarrubias S, Pradhan G, et al. Novel mutation and white matter involvement in an indian child with pycnodysostosis. Indian J Pediatr. 2015;82(5):471-473. doi:10.1007/s12098-014-1582-5.
150. Kumar S. A patient with pycnodysostosis presenting with seizures and porencephalic cysts. J Neurosci Rural Pract. 2014;5(3):284-286. doi:10.4103/0976-3147.133606.
151. Figueiredo J, Reis A, Vaz R, et al. Porencephalic cyst in pycnodysostosis. J Med Genet. 1989;26(12):782-784.
152. Bahl A, Olubajo F, Connolly D, et al. Sinus hypoplasia and intracranial hypertension in pycnodysostosis (shihp): a new disease process? Ann Paed Rheum. 2013;2(2):56-61. doi:10.5455/apr.011620131343.
153. Mujawar Q, Naganoor R, Patil H, et al. Pycnodysostosis with unusual findings: a case report. Cases J. 2009;2:6544. doi:10.4076/1757- 1626-2-6544.
154. Knight ZA, Shokat KM. Chemical genetics: where genetics and pharmacology meet. Cell. 2007;128(3):425-430. doi:10.1016/j. cell.2007.01.021.
155. Dufour A, Sampson NS, Zucker S, et al. Role of the hemopexin domain of matrix metalloproteinases in cell migration. J Cell Physiol. 2008;217(3):643-651. doi:10.1002/jcp.21535.
156. Bone HG, McClung M, Verbruggen N, et al. A randomized doubleblind, placibo-controlled study of cathepsin K inhibitor in the treatment of postmenopausal women with low bmd: one year results. J Bone Miner Res. 2008;22(Suppl. 1):S37.
157. Gelb BD, Brömme D, Desnick RJ. Pycnodysostosis: cathepsin K deficiency. In: Sriver CR, Beaudet AL, Valle D, et al., editors. The metabolic and molecular bases of inherited diseases. Vol. III, part 16. New York, St. Louis, San Francisco: McGraw-Hill. Inc; 2001. p. 3453- 3468.
158. Khan MP, Singh AK, Singh AK, et al. Odanacatib restores trabecular bone of skeletally mature female rabbits with osteopenia but induces brittleness of cortical bone: a comparative study of the investigational drug with pth, estrogen, and alendronate. J Bone Miner Res. 2015. doi:10.1002/jbmr.2719.
159. Whyte MP, Wenkert D, Clements KL, et al. Bisphosphonate-induced osteopetrosis. N Engl J Med. 2003;349(5):457-463. doi:10.1056/ NEJMoa023110.
160. Marx RE, Sawatari Y, Fortin M, et al. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg. 2005;63(11):1567-1575. doi:10.1016/j.joms.2005.07.010.
161. Gentile MA, Soung Do Y, Horrell C, et al. Increased fracture callus mineralization and strength in cathepsin K knockout mice. Bone. 2014;66:72-81. doi:10.1016/j.bone.2014.04.032.
162. Reddy GK, Dhar SC. Purification and characterization of collagenolytic property of renal cathepsin L from arthritic rat. Int J Biochem. 1992;24(9):1465-1473.
163. Kakegawa H, Nikawa T, Tagami K, et al. Participation of cathepsin L on bone resorption. FEBS Lett. 1993;321:247-250.
164. Everts V, Aronson DC, Beertsen W. Phagocytosis of bone collagen by osteoclasts in two cases of pycnodysostosis. Calcif Tissue Int. 1985;37:25-31.
165. Everts V, Hou WS, Rialland X, et al. Cathepsin K deficiency in pycnodysostosis results in accumulation of non-digested phagocytosed collagen in fibroblasts. Calcif Tissue Int. 2003;73(4):380-386. doi:10.1007/s00223-002-2092-4.
166. Daubine F, Cortial D, Ladam G, et al. Nanostructured polyelectrolyte multilayer drug delivery systems for bone metastasis prevention. Biomaterials. 2009;30(31):6367-6373. doi:10.1016/j. biomaterials.2009.08.002.
167. Elazar V, Adwan H, Bauerle T, et al. Sustained delivery and efficacy of polymeric nanoparticles containing osteopontin and bone sialoprotein antisenses in rats with breast cancer bone metastasis. Int J Cancer. 2010;126(7):1749-1760. doi:10.1002/ijc.24890.
168. Uludag H. Bisphosphonates as a foundation of drug delivery to bone. Curr Pharm Des. 2002;8(21):1929-1944.
169. Wang F, Chen L, Zhang R, et al. RGD peptide conjugated liposomal drug delivery system for enhance therapeutic efficacy in treating bone metastasis from prostate cancer. J Control Release. 2014;196:222-233. doi:10.1016/j.jconrel.2014.10.012.
170. Panwar P, Soe K, Guido RV, et al. A novel approach to inhibit bone resorption: exosite inhibitors against cathepsin K. Br J Pharmacol. 2016;173(2):396-410. doi:10.1111/bph.13383.
171. Hou W-S, Brömme D, Zhao Y, et al. Cathepsin K: characterization of novel mutations in the pro and mature polypeptide regions causing pycnodysostosis. J Clin Invest. 1999;103:731-738. doi:10.1172/ JCI653.
172. Mosekilde L, Torring O, Rejnmark L. Emerging anabolic treatments in osteoporosis. Curr Drug Saf. 2011;6(2):62-74.
173. Jia M, Nie Y, Cao DP, et al. Potential antiosteoporotic agents from plants: a comprehensive review. Evid Based Complement Alternat Med. 2012;2012:364604. doi:10.1155/2012/364604.
174. Senthilkumar K, Venkatesan J, Manivasagan P, et al. Antiangiogenic effects of marine sponge derived compounds on cancer. Environ Toxicol Pharmacol. 2013;36(3):1097-1108. doi:10.1016/j. etap.2013.09.014.
175. Leung P-C, Siu W-S. Herbal treatment for osteoporosis: a current review. J Tradit Complement Med. 2013;3(2):82-87. doi:10.4103/ 2225-4110.110407.
176. Guo Y, Li Y, Xue L, et al. Salvia miltiorrhiza: an ancient chinese herbal medicine as a source for anti-osteoporotic drugs. J Ethnopharmacol. 2014. doi:10.1016/j.jep.2014.07.058.
177. Verbovsek U, Van Noorden CJ, Lah TT. Complexity of cancer protease biology: cathepsin K expression and function in cancer progression. Semin Cancer Biol. 2015;35:71-84. doi:10.1016/j. semcancer.2015.08.010.