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Cathepsins K and S: Role in Bone, Adipocytes, and Glucose Regulation

  • Skeletal and calcium controversies in diabetes mellitus, cardiovascular disease, and lipid disorders
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Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Cathepsins are a diverse group of proteases that are increasingly being recognized for their role in various disease states. The focus of this article is to review the data regarding the activity of cathepsin K and cathepsin S in adipocyte differentiation and function as well as glucose metabolism. Data from animal and human studies have shown up-regulation of cathepsin K expression in white adipose tissue of overweight/obese mice and humans. Cathepsin K appears to affect adipocyte differentiation as well as weight gain. Data from studies using cathepsin K blocking agents suggest that by blocking cathepsin K, there is reduction in adipocyte differentiation and weight gain. Cathepsin K also may play a role in glucose metabolism with higher cathepsin K levels being associated with insulin resistance. Cathepsin S is also overexpressed in adipose tissue of overweight/obese subjects. Both murine and human models have been studied to further investigate its role in adipocytes and obesity. Cathepsin S appears to be involved in glucose dysregulation as well as pathogenesis of diabetes mellitus. Further studies are necessary to better characterize the role of cathepsin K and S and to examine whether there is potential for targeted therapy for prevention and treatment of obesity as well as diabetes mellitus.

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References

  1. Fonovic M, Turk B. Cysteine cathepsins and extracellular matrix degradation. Biochim Biophys Acta. 2014;1840:2560–70.

    Article  CAS  PubMed  Google Scholar 

  2. Rossi A, Deveraux Q, Turk B, Sali A. Comprehensive search for cysteine cathepsins in the human genome. Biol Chem. 2004;385:363–72.

    Article  CAS  PubMed  Google Scholar 

  3. Chen RP, Ren A, Ye SD. Correlation between serum cathepsin S and insulin resistance in type 2 diabetes. Exp Ther Med. 2013;6:1237–42.

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Vasiljeva O, Reinheckel T, Peters C, Turk D, Turk V, Turk B. Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Des. 2007;13:387–403.

    Article  CAS  PubMed  Google Scholar 

  5. Taleb S, Clement K. Emerging role of cathepsin S in obesity and its associated diseases. Clin Chem Lab Med. 2007;45(3):328–32.

    Article  CAS  PubMed  Google Scholar 

  6. Novinec M, Lenarčič B. Cathepsin K: a unique collagenolytic cysteine peptidase. Biol Chem. 2013;394(9):1163–79.

    Article  CAS  PubMed  Google Scholar 

  7. Sukhova GK, Shi G, Simon DI, Chapman HA, 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. 1998;102:576–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Hou WS, Li Z, Gordon RE, Chan K, Klein MJ, Levy R, et al. Cathepsin k is a critical protease in synovial fibroblast-mediated collagen degradation. Am J Pathol. 2001;159:2167–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Xiao Y, Junfeng H, Tianhong L, Lu W, Shulin C, Yu Z, Xiaohua L, Weixia J, Sheng Z, Yanyun G, Guo L, Min L. Cathepsin K in adipocyte differentiation and its potential role in pathogenesis of obesity. JCEM. 2006;91(11):4520–7.

    PubMed  Google Scholar 

  10. Littlewood-Evans AJ, Bilbe G, Bowler WB, Farley D, Wlodarski B, Kokubo T, et al. The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res. 1997;56:5386–90.

    Google Scholar 

  11. Brubaker KD, Vessella R, True LD, Thomas R, Corey E. Cathepsin K mRNA and protein expression in prostate cancer progression. J Bone Miner Res. 2003;18:222–30.

    Article  CAS  PubMed  Google Scholar 

  12. Zerbini CA, McClung M. Odanacatib in postmenopausal women with low bone mineral density: a review of current clinical evidence. Ther Adv Musculoskelet Dis. 2013;5:199–209.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Rieman DJ, McClung H, Dodds RA, Hwang SM, Holmes MW, James IE, et al. Biosynthesis and processing of cathepsin K in cultured human osteoclasts. Bone. 2001;28:282–9.

    Article  CAS  PubMed  Google Scholar 

  14. Das S, Crockett J. Osteoporosis—a current view of pharmacological prevention and treatment. Drug Des Devel Ther. 2013;7:435–48.

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Tezuka K, Tezuka Y, Maejima A, Sato T, Nemoto K, Kamioka H, Hakeda Y, Kumegawa M. Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts. J Biol Chem. 1994;269:1106–9.

    CAS  PubMed  Google Scholar 

  16. Brömme D, Lecaille F. Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert Opin Investig Drugs. 2009;18(5):585–600.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Chen W, Yang S, Abe Y, Li M, Wang Y, Shao J, et al. Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence. Hum Mol Genet. 2007;16:410–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Br T. The regulation of cathepsin K gene expression. Ann N Y Acad Sci. 2006;1068:165–72.

    Article  Google Scholar 

  19. Xue Y, Cai T, Shi S, Wang W, Zhang Y, Mao T, 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.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, et al. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res. 1999;14:1654–63.

    Article  CAS  PubMed  Google Scholar 

  21. Pennypacker B, Shea M, Liu Q, Masarachia P, Saftig P, Rodan S, et al. Bone density, strength, and formation in adult cathepsin K (−/−) mice. Bone. 2009;44:199–207.

    Article  CAS  PubMed  Google Scholar 

  22. Fratzl-Zelman N, et al. Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. JCEM. 2004;89(4):1538–47.

    CAS  PubMed  Google Scholar 

  23. McClung M. Odanacatib anti-fracture efficacy and safety in postmenopausal women with osteoporosis. Results from Phase III long-term odanacatib fracture trial (LOFT). ASBMR abstracts, 2014.

  24. Boonen S, Rosenberg E, Claessens F, Vanderschueren D, Papapoulos S. Inhibition of cathepsin K for treatment of osteoporosis. Curr Osteoporos Rep. 2012;10:73–9.

    Article  PubMed  Google Scholar 

  25. Falgueyret JP, Desmarais S, Oballa R, Black WC, Cromlish W, Khougaz K, 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;48:7535–43.

    Article  CAS  PubMed  Google Scholar 

  26. Runger TM, Adami S, Benhamou CL, Czerwinski E, Farrerons J, Kendler DL, et al. Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib. J Am Acad Dermatol. 2012;66:e89–96.

    Article  PubMed  Google Scholar 

  27. Medivir. 12/1/2014. www.medivir.com.

  28. Eastell R, Nagase S, Ohyama M, Small M, Sawyer J, Boonen S, et al. Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study. J Bone Miner Res. 2011;26:1303–12.

    Article  CAS  PubMed  Google Scholar 

  29. Gauthier JY, Chauret N, Cromlish W, Desmarais S, le Duong 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, Thérien 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(3):923–8.

    Article  CAS  PubMed  Google Scholar 

  30. Desmarais S, Massé 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):941–8.

    Article  CAS  PubMed  Google Scholar 

  31. Langdahl B, Binkley N, Bone H, Gilchrist N, Resch H, Rodriguez Portales J, 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;27:2251–8.

    Article  CAS  PubMed  Google Scholar 

  32. Bone HG, Dempster D, Eisman JA, Greenspan SL, McClung MR, Nakamura T 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.

  33. Rauner M, Föger-Samwald U, Kurz MF, Brünner-Kubath C, Schamall D, Kapfenberger A, Varga P, Kudlacek S, Wutzl A, Höger H, Zysset PK, Shi GP, Hofbauer LC, Sipos W, Pietschmann P. Cathepsin S controls adipocytic and osteoblastic differentiation, bone turnover, and bone microarchitecture. Bone. 2014;64:281–7.

    Article  CAS  PubMed  Google Scholar 

  34. Turk B, Turk V, Turk D. Structural and functional aspects of papain-like cysteine proteinases and their protein inhibitors. Biol Chem. 1997;378(3–4):141–50.

    CAS  PubMed  Google Scholar 

  35. Liu J, Ma L, Yang J, Ren A, Sun Z, Yan G, Sun J, Fu H, Xu W, Hu C, Shi GP. Increased serum cathepsin S in patient with atherosclerosis and diabetes. Atherosclerosis. 2006;186:411–9.

    Article  CAS  PubMed  Google Scholar 

  36. Clark AK, Yip P, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, Bevan S, Malcangio M. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. PNAS. 2007;104:10655–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Soukas A, Cohen P, Socci ND, Friedman JM. Leptin-specific patterns of gene expression in white adipose tissue. Genes Dev. 2000;14:963–80.

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Novelli S, Amri EZ, Benzi L, Bertacca A, Cohen P, Del Prato S, Friedman JM, Maffei M. Identification of Cathepsin K as a novel marker of adiposity in white adipose tissue. J Cell Physiol. 2003;194:309–21.

    Google Scholar 

  39. Yang M, Sun J, Zhang T, Liu J, Zhang J, Shi MA, Darakshan F, Guerre-Millo M, Clement K, Gelb BD, Dolgnov G, Shi GP. Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice. Arterioscler Thromb Vasc Biol. 2008;28:2202–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Naour N, Rouault C, Fellahi S, Lavoie ME, Poitou C, Keophiphath M, et al. Cathepsins in human obesity: changes in energy balance predominantly affect cathepsin S in adipose tissue and circulation. J Clin Endocrinol Metab. 2010;96:1861–8.

    Article  Google Scholar 

  41. Funicello M, Novelli M, Rangi M, Vottari T, Cocuzza C, Soriano-Lopez J, Chiellini C, Boschi F, Marzola P, Masiello P, Saftig P, Santini F, St-Jacques R, Desmrais S, Morin N, Mancini J, Percival MD, Pinchera A, Maffei M. Cathepsin K null mice showed reduced adiposity during the rapid accumulation of fat stores. PLoS One. 2007;2(8):e683.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Spiegelman BM, Ginty C. Fibronectin modulation of cell shape and lipogenic gene expression in 3T3-adipocytes. Cell. 1983;35:657–66.

    Article  CAS  PubMed  Google Scholar 

  43. Han J, Luo T, Gu Y, Li G, Jia W, Luo M. Cathepsin K regulates adipocyte differentiation: possible involvement of type I collagen degradation. Endocr J. 2009;56:55–63.

    Article  CAS  PubMed  Google Scholar 

  44. Jobs E, Risérus U, Ingelsson E, Sundström J, Jobs M, Nerpin E, Iggman D, Basu S, Larsson A, Lind L, Ärnlöv J. Serum cathepsin S is associated with decreased insulin sensitivity and the development of type 2 diabetes in a community-based cohort of elderly men. Diabetes Care. 2013;36(1):163–5.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Taleb S, Lacasa D, Bastard JP, Poitou C, Cancello R, Pelloux V, Viguerie N, Benis A, Zucker JD, Bouillot JL, Coussieu C, Basdevant A, Langin D, Clement K. Cathepsin S, a novel biomarker of adiposity: relevance to atherogenesis. FASEB J. 2002;19(11):1540–2.

    Google Scholar 

  46. Oliveira M, Assis D, Paschoalin T, Miranda A, Ribeiro EB, Juliano MA, Brömme D, Christoffolete MA, Barros NM, Carmona AK. Cysteine cathepsin S processes leptin, inactivating its biological activity. J Endocrinol. 2012;214(2):217–24.

    Article  CAS  PubMed  Google Scholar 

  47. Jobs E, Adamsson V, Larsson A, Jobs M, Nerpin E, Ingelsson E, Ärnlöv J, Risérus U. Influence of a prudent diet on circulating cathepsin S in humans. Nutr J. 2014;13:84.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Hsing LC, Kirk E, McMillen TS, et al. Roles for cathepsin S, L, and B in insulinitis and diabetes in the NOD mouse. J Autoimmun. 2010;34:96–104.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Taleb S, Cancello R, Poitou C, Rouault C, Sellam P, Levy P, Bouillot JL, Coussieu C, Basdevant A, Guerro-Millo M, Lacasa D, Clement K. Weight loss reduces adipose tissue cathepsin S and its circulating levels in morbidly obese women. J Clin Endocrinol Metab. 2006;91:1042–7.

    Article  CAS  PubMed  Google Scholar 

  50. Korpos E, Kadri N, Kappelhoff R, Wegner J, Overall CM, Weber E, Holmberg D, Cardell S, Sorokin L. The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human. Diabetes. 2013;62:531–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Duarte N, Stenström M, Campino S, et al. Prevention of diabetes in non-obese diabetic mice mediated by CD1d-restricted nonclassical NKT cells. J Immunol. 2004;173:3112–8.

    Article  CAS  PubMed  Google Scholar 

  52. Gonzalez A, Katz J, Mattei MG, Kikutani H, Benoist C, Mathis D. Genetic control of diabetes progression. Immunity. 1997;7:873–83.

    Article  CAS  PubMed  Google Scholar 

  53. Sorokin L. The impact of the extracellular matrix on inflammation. Nat Rev Immunol. 2010;10:712–23.

    Article  CAS  PubMed  Google Scholar 

  54. Reise RJ, Wolf P, Brömme D, et al. Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading. Immunity. 1996;4:357–66.

    Article  Google Scholar 

  55. Gocheva V, Wang H, Gadea BB, et al. IL-4 induced cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 2010;24:241–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Chang SH, Kanasaki K, Gocheva V, et al. VEGF-A induced angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation. Cancer Res. 2009;69:4537–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Abdul-Hussien H, Soekhoe R, Weber E, et al. Collagen degradation in the abdominal aneurysm: a conspiracy of matrix metalloproteinase and cysteine collagenases. Am J Pathol. 2007;170:809–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Wang B, Sun J, Kitamoto S, et al. Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. J Biol Chem. 2006;281:6020–9.

    Article  CAS  PubMed  Google Scholar 

  59. Reise RJ, Mitchell R, Villadango JA, Shi GP, Palmer JT, Karp ER, De Sanctis GT, Ploegh HL, Chapman HA. Cathepsin S activity regulates antigen presentation and immunity. J Clin Invest. 1998;101(11):2351–63.

    Article  Google Scholar 

  60. Ye Z, Wang S, Yang Z, et al. Serum lipocalin-2, cathepsin S and chemerin levels and nonalcoholic fatty liver disease. Mol Biol Rep. 2014;41:1317–23.

    Article  CAS  PubMed  Google Scholar 

  61. Trayhurn P, Wood I. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004;92:347–55.

    Article  CAS  PubMed  Google Scholar 

  62. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132:2169–80.

    Article  CAS  PubMed  Google Scholar 

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C. Wilczynski, S. Samarasinghe, M. A. Emanuele, N. Emanuele, L. Shah, A. Mazhari declare that they have no conflict of interest.

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  1. Loyola University Health System, Maywood, IL, USA

    C. Wilczynski, S. Samarasinghe, M. A. Emanuele, N. Emanuele, L. Shah & A. Mazhari

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  1. C. Wilczynski
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Wilczynski, C., Samarasinghe, S., Emanuele, M.A. et al. Cathepsins K and S: Role in Bone, Adipocytes, and Glucose Regulation. Clinic Rev Bone Miner Metab 13, 2–10 (2015). https://doi.org/10.1007/s12018-015-9177-x

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