The ClinicianThe ClinicianКлиницист1818-83382412-8775Publishing House ABV Press21310.17650/1818-8338-2012-6-2-9-16REVIEWОБЗОРTHE ROLE OF CYTOKINE SYSTEM RANKL-RANK-OPG AND CATHEPSIN K IN THE PATHOGENESIS OF OSTEOPOROSIS: ACHIEVEMENTS AND PERSPECTIVES IN THE TREATMENT OF DISEASEРОЛЬ ЦИТОКИНОВОЙ СИСТЕМЫ RANKL-RANK-OPG И КАТЕПСИНА К В ПАТОГЕНЕЗЕ ОСТЕОПОРОЗА: ДОСТИЖЕНИЯ И ПЕРСПЕКТИВЫ В ЛЕЧЕНИИ ЗАБОЛЕВАНИЯSagalovskyS.СагаловскиС.
Germany

Department of Orthopedics

Отделение ортопедии

stanislav.sagalovsky@median-kliniken.deKunzeP.КунцеП.
Germany

Department of Orthopedics

Отделение ортопедии

SchönertM.ШенертМ.
Germany

Department of Orthopedics

Отделение ортопедии

Median Klinik, Bad Lausick, GermanyКлиника Медиан, Бад Лаузик, Германия15042012629161510201515102015Copyright ©; 2012, Sagalovsky S., Kunze P., Schönert M.Copyright ©; 2012, Сагаловски С., Кунце П., Шенерт М.2012Sagalovsky S., Kunze P., Schönert M.Сагаловски С., Кунце П., Шенерт М.https://creativecommons.org/licenses/by/4.0https://klinitsist.abvpress.ru/Klin/article/view/213

The article presents review of literature dedicated to the contemporary view on the cellular-molecular mechanisms of the bone remodeling and pathogenesis of the osteoporosis. The discovery of the cytokine RANKL-RANK-OPG system and significant role of the cathepsin K in process bone remodeling has made progress in understanding the mechanisms development disease and possible to development drugs of the new generation – denosumab, a fully human RANKL monoclonal antibody and inhibitor cathepsin K odanacatib that inhibits of the bone resorption.

В обзоре литературы представлены современные взгляды на клеточно-молекулярные механизмы развития ремоделирования кости и патогенез остеопороза. Открытие цитокиновой системы RANKL-RANK-OPG и значительной роли катепсина К в процессе ремоделирования костной ткани внесло значительный прогресс в понимание механизмов развития остеопороза и позволило разработать препараты нового поколения – деносумаб, полностью человеческое моноклональное антитело к RANKL (receptor activator nucleus factor kappa B ligand), и ингибитор катепсина К оданакатиб, угнетающие процесс резорбции костной ткани.

bone remodelingsystem RANKL-RANK-OPGcathepsin Kosteoporosisdenosumabodanacatibремоделирование костисистема RANKL-RANK-OPGкатепсин Костеопорозденосумабоданакатиб1. World Health Organization. Assessment of fracture risk its application to screening for postmenopausal women. WHO Technical Report Series, 2007:843.World Health Organization. Assessment of fracture risk its application to screening for postmenopausal women. WHO Technical Report Series, 2007:843.2. Dhanwal D.K., Dennison E.M., Harvey N.C., Cooper C. Epidemiology of hip fracture: worldwide geographic variation. Indian J Orthop 2011;45:15–22.Dhanwal D.K., Dennison E.M., Harvey N.C., Cooper C. Epidemiology of hip fracture: worldwide geographic variation. Indian J Orthop 2011;45:15–22.3. Dennison E., Cooper C. Osteoporosis in 2010: building bones and (safely) preventing breaks. Nat Rev Rheumatol 2011;7:80–2.Dennison E., Cooper C. Osteoporosis in 2010: building bones and (safely) preventing breaks. Nat Rev Rheumatol 2011;7:80–2.4. Cole Z.A., Dennison E.M., Cooper C. Osteoporosis epidemiology update. Curr Rheumatol Rep 2008;10(2):92–6.Cole Z.A., Dennison E.M., Cooper C. Osteoporosis epidemiology update. Curr Rheumatol Rep 2008;10(2):92–6.5. Edelman E. Epidemiologie und gessellschaftliche Knochen der Osteoporose. Bad Aibling: 2009.Edelman E. Epidemiologie und gessellschaftliche Knochen der Osteoporose. Bad Aibling: 2009.6. Häussler B., Gothe H., Gol D. et al. Epidemiology, treatment and costs of osteoporosis in Germany – the BoneEVA Study. Osteoporos Int 2007;18(1):77–84.Häussler B., Gothe H., Gol D. et al. Epidemiology, treatment and costs of osteoporosis in Germany – the BoneEVA Study. Osteoporos Int 2007;18(1):77–84.7. Лесняк О.М., Беневоленская Л.И. Остеопороз в Российской Федерации: проблемы и перспективы. Научн. практ. ревматол 2010;(5):14–8.Лесняк О.М., Беневоленская Л.И. Остеопороз в Российской Федерации: проблемы и перспективы. Научн. практ. ревматол 2010;(5):14–8.8. Reda A., Bartoletti M.G. Osteoporosis: epidemiology, clinical and biological aspects. BMC Geriatrics 2010;10(Suppl 1):L71.Reda A., Bartoletti M.G. Osteoporosis: epidemiology, clinical and biological aspects. BMC Geriatrics 2010;10(Suppl 1):L71.9. Шостак Н.А. Остеопороз: настоящее и будущее. Клиницист 2006;(3):4–5.Шостак Н.А. Остеопороз: настоящее и будущее. Клиницист 2006;(3):4–5.10. IOF World Congress on Osteoporosis and 10th European Congress of Clinical and Economic aspects of Osteoporosis and Osteoarthritis. Plenary Lectures Abstracts. Osteoporosis Int 2010;21(Suppl 1):1–6.IOF World Congress on Osteoporosis and 10th European Congress of Clinical and Economic aspects of Osteoporosis and Osteoarthritis. Plenary Lectures Abstracts. Osteoporosis Int 2010;21(Suppl 1):1–6.11. Harvey N., Dennison E.M., Cooper C. Osteoporosis: impact on health and economics. Nat Rev Rheumatol 2010;6:99–105.Harvey N., Dennison E.M., Cooper C. Osteoporosis: impact on health and economics. Nat Rev Rheumatol 2010;6:99–105.12. Kanis J.A., Burlet N., Cooper C. et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporosis Int 2008;19(4):399–428.Kanis J.A., Burlet N., Cooper C. et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporosis Int 2008;19(4):399–428.13. Reginster J.Y. Antifracture efficacy of currently available therapies for postmenopausal osteoporosis. Drugs 2011;71(1):65–78.Reginster J.Y. Antifracture efficacy of currently available therapies for postmenopausal osteoporosis. Drugs 2011;71(1):65–78.14. Romas E. Corticosteroid-induced osteoporosis and fractures. Aust Prescr 2008;31:45–9.Romas E. Corticosteroid-induced osteoporosis and fractures. Aust Prescr 2008;31:45–9.15. Raggatt L.J., Partridge N.C. Cellular and molecular mechanisms of bone remodeling. J Biol Chem 2010;285(33):25103–8.Raggatt L.J., Partridge N.C. Cellular and molecular mechanisms of bone remodeling. J Biol Chem 2010;285(33):25103–8.16. Ziros P.G., Basdra E.K., Papavassiliou A.G. Runx2: of bone and stretch. Int J Biochem Cell Biol 2008;40(9):1659–63.Ziros P.G., Basdra E.K., Papavassiliou A.G. Runx2: of bone and stretch. Int J Biochem Cell Biol 2008;40(9):1659–63.17. Zhang X., Yang M., Lin L. et al. RUNX2 overexpression enhances osteoblasticZhang X., Yang M., Lin L. et al. RUNX2 overexpression enhances osteoblasticdifferentiation and mineralization in adipose-derived stem cells in vitro and in vivo. Calcif Tissue Int 2006;79:169–78.18. Merciris D., Marty C., Collet C. et al. Overexpression of the transcriptional factor RUNX2 in osteoblasts abolishes the anabolic effect of parathyroid hormone in vivo. Am J Pathol 2007;170:1676–85.Merciris D., Marty C., Collet C. et al. Overexpression of the transcriptional factor RUNX2 in osteoblasts abolishes the anabolic effect of parathyroid hormone in vivo. Am J Pathol 2007;170:1676–85.19. Tu Q., Zhang J., James L. et al. Cbfa1/Runx2-deficiency delays bone wound healing and locally delivered Cbfa1/Runx2 promotes bone repair in animal models. Wound Repair Regen 2007;15:404–12.Tu Q., Zhang J., James L. et al. Cbfa1/Runx2-deficiency delays bone wound healing and locally delivered Cbfa1/Runx2 promotes bone repair in animal models. Wound Repair Regen 2007;15:404–12.20. Jacob F., Seefried L., Ebert R. Pathophysiology of bone metabolism. Internist 2008;49:1159–69.Jacob F., Seefried L., Ebert R. Pathophysiology of bone metabolism. Internist 2008;49:1159–69.21. Umland E.M. An update on osteoporosis epidemiology and bone physiology. Univer Tennessee Adv Stud Pharmacy 2008;5(7):210–4.Umland E.M. An update on osteoporosis epidemiology and bone physiology. Univer Tennessee Adv Stud Pharmacy 2008;5(7):210–4.22. Kearns A.E., Khosla S., Kosteniuk P.G. Receptor activator of nuclear factor kappa B ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008;29:155–92.Kearns A.E., Khosla S., Kosteniuk P.G. Receptor activator of nuclear factor kappa B ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008;29:155–92.23. Trouvin A.P., Goеb V. Receptor activatorTrouvin A.P., Goеb V. Receptor activatorof nuclear factor-kB ligand and osteoprotegerin: maintaining the balance to prevent bone loss. Clin Intervent Aging 2010;5:345–354.24. Lee M.S., Kim H.S., Yeon J.T. et al. GM-CSF regulates fusion of mononuclear osteoclasts into bone-resorbing osteoclasts by activating the Ras/ERK pathway. J Immunol 2009;183:3390–9.Lee M.S., Kim H.S., Yeon J.T. et al. GM-CSF regulates fusion of mononuclear osteoclasts into bone-resorbing osteoclasts by activating the Ras/ERK pathway. J Immunol 2009;183:3390–9.25. Kollias G., Sfikakis P.P. (eds.). TNF: pathophysiology, molecular and cellular mechanisms. Basel: Karger AG; 2010.Kollias G., Sfikakis P.P. (eds.). TNF: pathophysiology, molecular and cellular mechanisms. Basel: Karger AG; 2010.26. Hofbauer L., Rachner T. Die rolle des RANKL-RANK-OPG-SignalwegsHofbauer L., Rachner T. Die rolle des RANKL-RANK-OPG-Signalwegsin Knochenstoffwechsel. Forbildung Osteologie 2010;3:118–21.27. Sarahrudi K., Mousavi M., Thomas A. et al. Elevated levels of macrophage colony-stimulating factor in human fracture healing. J Orthoped Res 2010;28(5):671–6.Sarahrudi K., Mousavi M., Thomas A. et al. Elevated levels of macrophage colony-stimulating factor in human fracture healing. J Orthoped Res 2010;28(5):671–6.28. Imai Y., Kondoh S., Kouzmenko A., Kato S. Minireview: osteoprotective action of estrogenes is mediated by osteoclastic estrogen receptor-alpha. Mol Endocrinol 2010;24:877–85.Imai Y., Kondoh S., Kouzmenko A., Kato S. Minireview: osteoprotective action of estrogenes is mediated by osteoclastic estrogen receptor-alpha. Mol Endocrinol 2010;24:877–85.29. Weitzmann N.M., Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest 2006;116(5):1186–94.Weitzmann N.M., Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest 2006;116(5):1186–94.30. Jabbar S., Drury J., Fordham J.N. et al. Osteoprotegerin, RANKL and bone turnover in postmenopausal osteoporosis. J Clin Pathol 2011;64:354–7.Jabbar S., Drury J., Fordham J.N. et al. Osteoprotegerin, RANKL and bone turnover in postmenopausal osteoporosis. J Clin Pathol 2011;64:354–7.31. Darnay B.G., Besse A., Poblenz A. et al. TRAFs in RANK signaling. Adv Exp Med Biol 2007;597:152–9.Darnay B.G., Besse A., Poblenz A. et al. TRAFs in RANK signaling. Adv Exp Med Biol 2007;597:152–9.32. Zhao Q., Wang X., Liu Y. et al. NFATc1: functions in osteoblasts. Int J Biochem Cell Biol 2010;42:576–9.Zhao Q., Wang X., Liu Y. et al. NFATc1: functions in osteoblasts. Int J Biochem Cell Biol 2010;42:576–9.33. Wadas T.J., Deng H., Sprague J.E. et al. Targeting the avb3 integrin for small-animal PET/CT of osteolytic bone metastases. J Nucl Med 2009;50:1873–80.Wadas T.J., Deng H., Sprague J.E. et al. Targeting the avb3 integrin for small-animal PET/CT of osteolytic bone metastases. J Nucl Med 2009;50:1873–80.34. McClung M. Cathepsin K inhibitors: a unique mechanism of action for the treatment of osteoporosis. Oregon: Williams and Wilkins; 2009.McClung M. Cathepsin K inhibitors: a unique mechanism of action for the treatment of osteoporosis. Oregon: Williams and Wilkins; 2009.35. Kato S. Hormones and osteoporosis update. Estrogen and bone remodeling. Clin Calcium 2009;19:951–6.Kato S. Hormones and osteoporosis update. Estrogen and bone remodeling. Clin Calcium 2009;19:951–6.36. Hikiji H., Takato T., Shimizu T., Ishii S. The roles of prostanoids, leukotrienes and platelet-activating factor in bone metabolism and disease. Prog Lipid Res 2008;47:107–26.Hikiji H., Takato T., Shimizu T., Ishii S. The roles of prostanoids, leukotrienes and platelet-activating factor in bone metabolism and disease. Prog Lipid Res 2008;47:107–26.37. Lee Y.-M., Fujukado N., Manaka H. et al. IL-1 plays an important role in the bone metabolism under physiological conditions. Int Immunol 2010;22:805–16.Lee Y.-M., Fujukado N., Manaka H. et al. IL-1 plays an important role in the bone metabolism under physiological conditions. Int Immunol 2010;22:805–16.38. Fujisaki K., Tanabe N., Suzuki N. et al. Receptor activator of NF-kappa B ligand induced the expression of carbonic anhydrase II, cathepsin K, and matrix metalloproteinase-9 in osteoclast precursor RAW 264-7 cells. Life Sci 2007;80:1311–8.Fujisaki K., Tanabe N., Suzuki N. et al. Receptor activator of NF-kappa B ligand induced the expression of carbonic anhydrase II, cathepsin K, and matrix metalloproteinase-9 in osteoclast precursor RAW 264-7 cells. Life Sci 2007;80:1311–8.39. Pennypacker B., Shea M., Liu Q. et al. Bone density, strength, and formation in adult cathepsin K (-/-) mice. Bone 2009;44:199–207.Pennypacker B., Shea M., Liu Q. et al. Bone density, strength, and formation in adult cathepsin K (-/-) mice. Bone 2009;44:199–207.40. Vega D., Maalouf N.M., Sakhaee K. Clinical review: the role of receptor activator of nuclear factor-kappa B (RANK) ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab 2007;92:4514–21.Vega D., Maalouf N.M., Sakhaee K. Clinical review: the role of receptor activator of nuclear factor-kappa B (RANK) ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab 2007;92:4514–21.41. Hamdy N.A. Osteoprotegerin as a pot ential therapy for osteoporosis. Curr Rheumatol Rep 2006;8:50–4.Hamdy N.A. Osteoprotegerin as a pot ential therapy for osteoporosis. Curr Rheumatol Rep 2006;8:50–4.42. Preisinger E. RANK/RANK-Ligand/OPG: Ein neuer Therapieansatz in der Osteoporosebehandlung. J Miner Stoffwechs 2007;14:144–5.Preisinger E. RANK/RANK-Ligand/OPG: Ein neuer Therapieansatz in der Osteoporosebehandlung. J Miner Stoffwechs 2007;14:144–5.43. Gehrig L, Lane J, O'Connor M. Osteoporosis: management and treatment strategies for orthopaedic surgeons. J Bone Joint Surg Am 2008;90(6):1362–74.Gehrig L, Lane J, O'Connor M. Osteoporosis: management and treatment strategies for orthopaedic surgeons. J Bone Joint Surg Am 2008;90(6):1362–74.44. Yang R.S., Liu S.H. Current pharmacological approaches to prevent and treat postmenopausal osteoporosis. Recent Patents on Endocrine. Metabolic& Immune Drug Discovery 2009;3:42–53.Yang R.S., Liu S.H. Current pharmacological approaches to prevent and treat postmenopausal osteoporosis. Recent Patents on Endocrine. Metabolic& Immune Drug Discovery 2009;3:42–53.45. Sugimoto T. Anti-RANKL monoclonal antibody denosumab (AMG 162). Clin Calcium 2011;21:46–51.Sugimoto T. Anti-RANKL monoclonal antibody denosumab (AMG 162). Clin Calcium 2011;21:46–51.46. Varenna M., Gatti D. The role of RANK-ligand inhibition in the treatment of postmenopausal osteoporosis. Reumatismo 2010;62:163–71.Varenna M., Gatti D. The role of RANK-ligand inhibition in the treatment of postmenopausal osteoporosis. Reumatismo 2010;62:163–71.47. Helas S., Göttsch C., Schoppet et al. Inhibition of receptor activator of NF-kappa B ligand by denosumab attenuates vascular calcium deposition in mice. Am J Pathol 2009;175:473–8.Helas S., Göttsch C., Schoppet et al. Inhibition of receptor activator of NF-kappa B ligand by denosumab attenuates vascular calcium deposition in mice. Am J Pathol 2009;175:473–8.48. Kosteniuk P.J., Nguyen H.Q., McCabe J. et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Viner Res 2009;24(2):182–95.Kosteniuk P.J., Nguyen H.Q., McCabe J. et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Viner Res 2009;24(2):182–95.49. Lewiecki E.M. Clinical use of denosumabLewiecki E.M. Clinical use of denosumabfor the treatment for postmenopausal osteoporosis. Curr Med Res Opin 2010;26:2807–12.50. Cummings S.R., San Martin J., McClung M.R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65.Cummings S.R., San Martin J., McClung M.R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65.51. Moen M.D., Keam S.J. Denosumab: a review of its use in the treatment of postmenopausal osteoporosis. Drug Aging 2011;28:63–82.Moen M.D., Keam S.J. Denosumab: a review of its use in the treatment of postmenopausal osteoporosis. Drug Aging 2011;28:63–82.52. Brown J.P., Prince R.L., Deal C. et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J. Bone Miner Res 2009;24:153–61.Brown J.P., Prince R.L., Deal C. et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J. Bone Miner Res 2009;24:153–61.53. Kendler D.L., Roux C, Benhamou C.L. et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women trasitioning from alendronate therapy. J Bone Miner Res 2010;25:72–81.Kendler D.L., Roux C, Benhamou C.L. et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women trasitioning from alendronate therapy. J Bone Miner Res 2010;25:72–81.54. Baron R., Ferrari S., Russel R.G. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 2011;48:677–92.Baron R., Ferrari S., Russel R.G. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 2011;48:677–92.55. Leonard M., Lehmann M.K., White D.A., Wyman M Denosumab: a new therapy for osteoporosis. Pharmacotherapy Update 2010;13:10–9.Leonard M., Lehmann M.K., White D.A., Wyman M Denosumab: a new therapy for osteoporosis. Pharmacotherapy Update 2010;13:10–9.56. Mikosch P. Osteoporosetherapie mit Denosumab: 6-Jahres-Daten zu Knochendichte, Knochenumsatz und Verträglichkeit. J für Mineralstoffwechsel 2011;18(1):56–7.Mikosch P. Osteoporosetherapie mit Denosumab: 6-Jahres-Daten zu Knochendichte, Knochenumsatz und Verträglichkeit. J für Mineralstoffwechsel 2011;18(1):56–7.57. Nagase Y., Tanaka S. Odanacatib (MK-0822). Clin Calcium 2011;21:59–62.Nagase Y., Tanaka S. Odanacatib (MK-0822). Clin Calcium 2011;21:59–62.58. McCormick R.K.. Osteoporosis: integrating biomarkers and other diagnostic correlates into the management of bone fragility. Altern Med Rev 2007;12:113–45.McCormick R.K.. Osteoporosis: integrating biomarkers and other diagnostic correlates into the management of bone fragility. Altern Med Rev 2007;12:113–45.59. Perez-Castrillon J.L., Pinacho F., De Luis D. et al. Odanacatib, a new drug for the treatment of osteoporosis: review of the results in postmenopausal women. J Osteoporos 2010:pii 401581.Perez-Castrillon J.L., Pinacho F., De Luis D. et al. Odanacatib, a new drug for the treatment of osteoporosis: review of the results in postmenopausal women. J Osteoporos 2010:pii 401581.60. Eisman J.A., Bone H.G., Hosking D.J. 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 2011;26(2):242–51.Eisman J.A., Bone H.G., Hosking D.J. 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 2011;26(2):242–51.