Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2013

Open Access 01-12-2013 | Research article

Cathepsin K inhibitors increase distal femoral bone mineral density in rapidly growing rabbits

Authors: Brenda L Pennypacker, Renata M Oballa, Sonia Levesque, Donald B Kimmel, Le T Duong

Published in: BMC Musculoskeletal Disorders | Issue 1/2013

Login to get access

Abstract

Background

Selective and reversible inhibitors of human Cathepsin K (CatK), including odanacatib (ODN), have been developed as potential therapeutics for the treatment of osteoporosis. Inhibitors of human CatK show significantly less potency for the rodent enzymes compared with that for the human or rabbit enzymes; thus the Schenk model in growing rabbit was developed as a screening assay for the in vivo activity of CatK inhibitors in blocking bone resorption.

Methods

In this study, the efficacy of the selective inhibitors L-833905, L-006235, L-873724, and L-1037536 (ODN) of human CatK in the rapidly growing rabbit ‘Schenk’ model (age seven weeks) was compared to vehicle, using the bisphosphonate, alendronate (ALN), as a positive control, to assess inhibition of bone resorption. An enzyme inhibition assay (EIA) and an in vitro bone resorption assay using rabbit osteoclasts on bovine cortical bone slices were performed to evaluate the potency of these CatK inhibitors. Bone mineral density of the distal femur (DFBMD) was measured after ten days of treatment using ex vivo DXA densitometry.

Results

Results of the EIA using rabbit CatK and the rabbit bone resorption assay showed that three of the four compounds (L-006235, L-873724, and ODN) had similar potencies in the reduction of collagen degradation. L-833905 appeared to be a weaker inhibitor of CatK. Taking into account the respective in vitro potencies and pharmacokinetic profiles via oral administration, the efficacy of these four CatK inhibitors was demonstrated in a dose-related manner in the growing rabbit. Significant increases in DFBMD in animals dosed with the CatK inhibitors compared to vehicle were seen.

Conclusions

Efficacy of the CatK inhibitors in the Schenk rabbit correlated well with that in the in vitro rabbit bone resorption assay and in the ovariectomized rabbit model as previously published. Hence, these studies validated the rabbit Schenk assay as a rapid and reliable in vivo model for prioritizing human CatK inhibitors as potential therapeutic agents.
Appendix
Available only for authorised users
Literature
1.
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: 379-384. 10.1515/bchm3.1995.376.6.379.CrossRefPubMed
2.
Kafienah W, Brömme D, Buttle DJ, Croucher LJ, Hollander AP: Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem J. 1998, 331 (Pt 3): 727-732.CrossRefPubMedPubMedCentral
3.
Gelb BD, Shi GP, Chapman HA, Desnick RJ: Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996, 273: 1236-1238. 10.1126/science.273.5279.1236.CrossRefPubMed
4.
Ho N, Punturieri A, Wilkin D, Szabo J, Johnson M, Whaley J, Davis J, Clark A, Weiss S, Francomano C: Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein. J Bone Miner Res. 1999, 14: 1649-1653. 10.1359/jbmr.1999.14.10.1649.CrossRefPubMed
5.
Johnson MR, Polymeropoulos MH, Vos HL, De Luna RI O, Francomano CA: A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. Genome Res. 1996, 6: 1050-1055. 10.1101/gr.6.11.1050.CrossRefPubMed
6.
Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, Moritz JD, Schu P, Von Figura K: Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci USA. 1998, 95: 13453-13458. 10.1073/pnas.95.23.13453.CrossRefPubMedPubMedCentral
7.
Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I: Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res. 1999, 14: 1654-1663. 10.1359/jbmr.1999.14.10.1654.CrossRefPubMed
8.
Pennypacker B, Shea M, Liu Q, Masarachia P, Saftig P, Rodan S, Rodan G, Kimmel D: Bone density, strength, and formation in adult cathepsin K (−/−) mice. Bone. 2009, 44: 199-207. 10.1016/j.bone.2008.08.130.CrossRefPubMed
9.
Kiviranta R, Morko J, Uusitalo H, Aro HT, Vuorio E, Rantakokko J: Accelerated turnover of metaphyseal trabecular bone in mice overexpressing cathepsin K. J Bone Miner Res. 2001, 16: 1444-1452. 10.1359/jbmr.2001.16.8.1444.CrossRefPubMed
10.
Boonen S, Rosenberg E, Claessens F, Vanderschueren D, Papapoulos S: Inhibition of cathepsin K for treatment of osteoporosis. Curr Osteoporos Rep. 2012, 10: 73-79. 10.1007/s11914-011-0085-9.CrossRefPubMed
11.
Thompson DD, Simmons HA, Pirie CM, Ke HZ: FDA Guidelines and animal models for osteoporosis. Bone. 1995, 17: 125S-133S.CrossRefPubMed
12.
Stroup GB, Lark MW, Veber DF, Bhattacharyya A, Blake S, Dare LC, Erhard KF, Hoffman SJ, James IE, Marquis RW, Ru Y, Vasko-Moser JA, Smith BR, Tomaszek T, Gowen M: Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate. J Bone Miner Res. 2001, 16: 1739-1746. 10.1359/jbmr.2001.16.10.1739.CrossRefPubMed
13.
Falgueyret JP, Desmarais S, Oballa R, Black WC, Cromlish W, Khougaz K, Lamontagne S, Massé F, Riendeau D, Toulmond S, Percival MD: Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J Med Chem. 2005, 48: 7535-7543. 10.1021/jm0504961.CrossRefPubMed
14.
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: 941-948.CrossRefPubMed
15.
Pennypacker BL, Duong Le T, Cusick TE, Masarachia PJ, Gentile MA, Gauthier JY, Black WC, Scott BB, Samadfam R, Smith SY, Kimmel DB: Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits. J Bone Miner Res. 2011, 26: 252-262. 10.1002/jbmr.223.CrossRefPubMed
16.
Schenk R, Merz WA, Muhlbauer R, Russell RG, Fleisch H: Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl 2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calcif Tissue Res. 1973, 11: 196-214. 10.1007/BF02547219.CrossRefPubMed
17.
Miller SC, Jee WS: Ethane-1-hydroxy-1, 1-diphosphonate (EHDP). Effects on growth and modeling of the rat tibia. Calcif Tissue Res. 1975, 18: 215-231. 10.1007/BF02546241.CrossRefPubMed
18.
Schenk R, Eggli P, Fleisch H, Rosini S: Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat. Calcif Tissue Int. 1986, 38: 342-349. 10.1007/BF02555748.CrossRefPubMed
19.
Spadaro JA, Damron TA, Horton JA, Margulies BS, Murray GM, Clemente DA, Strauss JA: Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge. J Orthop Res. 2006, 24: 936-944. 10.1002/jor.20145.CrossRefPubMed
20.
Kuhn JL, DeLacey JH, Leenellett EE: Relationship between bone growth rate and hypertrophic chondrocyte volume in New Zealand white rabbits of varying ages. J Orthop Res. 1996, 14: 706-711. 10.1002/jor.1100140505.CrossRefPubMed
21.
Lerner AL, Kuhn JL: Characterization of regional and age-related variations in the growth of the rabbit distal femur. J Orthop Res. 1997, 15: 353-361. 10.1002/jor.1100150307.CrossRefPubMed
22.
Falgueyret JP, Black WC, Cromlish W, Desmarais S, Lamontagne S, Mellon C, Riendeau D, Rodan S, Tawa P, Wesolowski G, Bass KE, Venkatraman S, Percival MD: An activity-based probe for the determination of cysteine cathepsin protease activities in whole cells. Anal Biochem. 2004, 335: 218-227. 10.1016/j.ab.2004.09.005.CrossRefPubMed
23.
Falgueyret JP, Oballa RM, Okamoto O, Wesolowski G, Aubin Y, Rydzewski RM, Prasit P, Riendeau D, Rodan SB, Percival MD: Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L. J Med Chem. 2001, 44: 94-104. 10.1021/jm0003440.CrossRefPubMed
24.
Robichaud J, Oballa R, Prasit P, Falgueyret JP, Percival MD, Wesolowski G, Rodan SB, Kimmel D, Johnson C, Bryant C, Venkatraman S, Setti E, Mendonca R, Palmer JT: A novel class of nonpeptidic biaryl inhibitors of human cathepsin K. J Med Chem. 2003, 46: 3709-3727. 10.1021/jm0301078.CrossRefPubMed
25.
Gauthier JY, Chauret N, Cromlish W, Desmarais S, Duong Le T, Falgueyret JP, Kimmel DB, Lamontagne S, Léger S, LeRiche T, Li CS, Massé F, McKay DJ, Nicoll-Griffith DA, Oballa RM, Palmer JT, Percival MD, Riendeau D, Robichaud J, Rodan GA, Rodan SB, Seto C, Therien M, Truong VL, Venuti MC, Wesolowski G, Young RN, Zamboni R, Black WC: The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008, 18: 923-928. 10.1016/j.bmcl.2007.12.047.CrossRefPubMed
26.
Leung P, Pickarski M, Zhuo Y, Masarachia PJ, Duong LT: The effects of the cathepsin K inhibitor odanacatib on osteoclastic bone resorption and vesicular trafficking. Bone. 2011, 49: 623-635. 10.1016/j.bone.2011.06.014.CrossRefPubMed
27.
Kumar S, Dare L, Vasko-Moser JA, James IE, Blake SM, Rickard DJ, Hwang SM, Tomaszek T, Yamashita DS, Marquis RW, Oh H, Jeong JU, Veber DF, Gowen M, Lark MW, Stroup G: 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: 122-131. 10.1016/j.bone.2006.07.015.CrossRefPubMed
28.
Ochi Y, Yamada H, Mori H, Nakanishi Y, Nishikawa S, Kayasuga R, Kawada N, Kunishige A, Hashimoto Y, Tanaka M, Sugitani M, Kawabata K: Effects of ONO-5334, a novel orally-active inhibitor of cathepsin K, on bone metabolism. Bone. 2011, 49: 1351-1356. 10.1016/j.bone.2011.09.041.CrossRefPubMed
29.
Stroup GB, Hoffman SJ, Vasko-Moser JA, Lechowska BA, Jenkins EL, Dare LC, Gowen M: Changes in bone turnover following gonadotropin-releasing hormone (GnRH) agonist administration and estrogen treatment in cynomolgus monkeys: a short-term model for evaluation of antiresorptive therapy. Bone. 2001, 28: 532-537. 10.1016/S8756-3282(01)00421-5.CrossRefPubMed
30.
Sietsema WK, Ebetino FH, Salvagno AM, Bevan JA: Antiresorptive dose–response relationships across three generations of bisphosphonates. Drugs Exp Clin Res. 1989, 15: 389-396.PubMed
31.
Muhlbauer RC, Bauss F, Schenk R, Janner M, Bosies E, Strein K, Fleisch H: BM 21.0955, a potent new bisphosphonate to inhibit bone resorption. J Bone Miner Res. 1991, 6: 1003-1011.CrossRefPubMed
32.
Masarachia PJ, Pennypacker BL, Pickarski M, Scott KR, Wesolowski GA, Smith SY, Samadfam R, Goetzmann JE, Scott BB, Kimmel DB, Duong IT: Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys. J Bone Miner Res. 2012, 27: 509-523. 10.1002/jbmr.1475.CrossRefPubMed
33.
Cusick T, Chen CM, Pennypacker BL, Pickarski M, Kimmel DB, Scott BB, Duong IT: 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: 524-537. 10.1002/jbmr.1477.CrossRefPubMed
Metadata
Title
Cathepsin K inhibitors increase distal femoral bone mineral density in rapidly growing rabbits
Authors
Brenda L Pennypacker
Renata M Oballa
Sonia Levesque
Donald B Kimmel
Le T Duong
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2013
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/1471-2474-14-344

Other articles of this Issue 1/2013

BMC Musculoskeletal Disorders 1/2013 Go to the issue

Research article

Muscle activity and head kinematics in unconstrained movements in subjects with chronic neck pain; cervical motor dysfunction or low exertion motor output?

Research article

Comparing radiation exposure during percutaneous vertebroplasty using one- vs. two-fluoroscopic technique

Study protocol

Predicting response to physiotherapy treatment for musculoskeletal shoulder pain: protocol for a longitudinal cohort study

Study protocol

Maintaining endotracheal tube cuff pressure at 20 mm Hg to prevent dysphagia after anterior cervical spine surgery; protocol of a double-blind randomised controlled trial

Research article

The application of central tension plate with sharp hook in the treatment of intra-articular olecranon fracture

Research article

Bilateral increase in expression and concentration of tachykinin in a unilateral rabbit muscle overuse model that leads to myositis