BONE REMODELING IN NORM AND IN PRIMARY OSTEOPOROSIS: THE SIGNIFICANCE OF BONE REMODELING MARKERS

Osteoporosis is a systemic skeletal disease is characterized by low bone mass and microarchitectural deterioration of bone tissues, leading to bone fragility and low-energy The incidence of osteoporosis has risen because the life expectancy of the population has been increasing . Osteoporosis is an extremely common disease: osteoporosis affects more than 200million people worldwide and causes more than 8.9 million fractures. In Russia, among people aged 50 years and older, osteoporosis is diagnosed in 34% of women and 27% of men. The social significance of osteoporosis is determined by its consequences — fractures of the bones of the peripheral skeleton and vertebral fractures, leading to high material costs and causing a high level of disability and mortality. The normal physiological process of bone remodeling involves a balance between bone resorption and bone formation. In osteoporosis, this process becomes unbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several signaling pathways underlying primary osteoporosis have been identified, such as the osteoprotegerin/ receptor activator of nuclear factor kappa-B (RANK)/RANK ligand(RANKL), bone morphogenetic proteins, canonical wnt-signaling pathway. In addition, genetic disorders are involved in the development of the pathogenesis of osteoporosis. To identify osteoporosis, WHO recommends the use of dualenergy X-ray absorptive densitometry, which allows you to study the quantitative characteristics of bone tissue. Currently, there are various methods for evaluation of the quality of bone (microarchitectonics, the ability of bone tissue to be resistant to fracture), but these methods have limitations such as high cost and limited availability for their widespread using. The study of markers of bone remodeling in norm and in pathology helps to assess the quality of bone tissue indirectly, gives prospects in the selection of targeted therapy and improvement of early diagnosis of osteoporosis. 

1. Kanis J.A., on behalf of the WHO Scientific Group. Assessment of osteoporosis at the primary health-care level. Technical Report. WHO Collaboraiting Centre, University of Sheffield, UK, 2008

2. Pisani P, Renna MD, Conversano F et al. Major osteoporotic fragility fractures: risk factor updates and societal impact. World J Orthop. 2016; 7: 171.

3. Дедов И.И., Мельниченко Г.А., Белая Ж.Е. и др. Остеопороз. Клинические рекомендации. 2016; 104 с. I.I. Dedov, G.A. Melnichenko, J.E. Belaya et al. Osteoporosis. Clinical recommendations. 2016; 104 p. [in Russian].

4. Kuo T.R., Chen C.H. Bone biomarker for the clinical assessment of osteoporosis: recent developments and future perspectives. Biomark Res. 2017; 5: 18. doi: 10.1186/s40364-017-0097-4.

5. Harvey N.C., Gluer C.C., Binkley N. et al. Trabecular bone score (TBS) as a new complementary approach for osteoporosis evaluation in clinical practice. Bone 2015; 78: 216–224.

6. Patsch J.M., Burghardt A.J., Kazakia G. et al. Noninvasive imaging of bone microarchitecture. Ann NY Acad Sci 2011; 1240: 77–87. doi: 10.1111/j.1749-6632.2011.

7. Gomes C.C., Freitas D.Q, Medeiros Araújo A.M. et al. Effect of Alendronate on Bone Microarchitecture in Irradiated Rats With Osteoporosis: Micro-CT and Histomorphometric Analysis. J. Oral Maxillofac Surg. 2017. pii: S0278-2391(17)31439-8. doi: 10.1016/j.joms.2017.11.019.

8. Arnold M., Zhao S., Ma S. et al. Microindentation — a tool for measuring cortical bone stiffness? A systematic review. Bone Joint Res. 2017; 6(9): 542-549. doi: 10.1302/2046-3758.69.BJR-2016-0317.R2.

9. Cardoso L., Herman B.C., Verborgt O. et al. Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J. Bone Mineral Res. J Bone Miner Res. 2009; 24(4): 597-605. doi: 10.1359/jbmr.081210.

10. Остеопороз. Диагностика и лечение. / под ред. Дейла Стоувэлла; пер. с англ. под ред. О.М. Лесняк. М: ГЭОТАР — Медиа. 2015; 288 с. Edited by Dale Stowewall; trans. with English. Ed.O. Lesnyak. Osteoporosis. Diagnosis and treatment. M: GEOTAR — Media. 2015; 288 p. [in Russian].

11. Marotti G., Ferretti M., Muflia M.A. et al. A quantitive evaluation of osteoblast-osteocyte relationships on growing endosteal surface on rabbit tibiae. Bone. 1992; 13: 363-368.

12. Eriksen E.F. Cellular mechanisms of bone remodeling. Rev Endocr Metab Disord. 2010; 11(4): 219-227. doi: 10.1007/s11154-010-9153-1.

13. Brandi M.L., Collin-Osdoby P. Vascular biology and the skeleton. J Bone Miner Res. 2006; 21(2): 183-192. doi: 10.1359/JBMR.050917

14. Veilette C.J., von Schroeder H.P. Endothelin-1 down-regulates the expression of vascular endothelial growth factor-A associated with osteoprogenitorproliferation and differentiation. Bone. 2004; 34(2): 288-296. doi: 10.1016/j.bone.2003.10.009

15. Lian J.B., Stein G.S., Javed A. et al. Networks and hubs for the transcriptional control of osteoblastogenesis. Rev Endocr Metab Disord. 2006; 7(1-2): 1-16. doi: 10.1007/s11154-006-9001-5.

16. Wang Z.M., Luo J.Q., Xu L.Y. et al. Harnessing low-density lipoprotein receptor protein 6 (LRP6) genetic variation and Wnt signaling for innovative diagnostics in complex diseases. Pharmacogenomics J. 2017. doi: 10.1038/tpj.2017.28.

17. Майлян Э.А. Мультифакторность этиопатогенеза остеопороза и роль генов канонического WNT-сигнального пути. Остеопороз и остеопатии. 2015; 2: 15-19. Maylyan E.A.. Multifactority of etiopathogenesis of osteoporosis and the role of genes of the canonical WNT-signaling pathway. Osteoporosis and osteopathy. 2015; 2: 15-19 [in Russian].

18. Белая Ж.Е. WNT-сигнальный путь в исследованиях костной ткани. Остеопороз и остеопатии. 2016; 1: 13-14. Belaya J.E.. WNT-signaling pathway in studies of bone. Osteoporosis and osteopathy. 2016; 1: 13-14 [in Russian].

19. Гребенникова Т.А., Белая Ж.Е., Рожинская Л.Я. и др. Эпигенетические аспекты остеопороза. Вестник РАМН. 2015; 70 (5): 541–548. doi: 10.15690/vramn.v70.i5.1440. Grebennikova T.A., Belaya Zh.E., Rozhinskaya L.Ya. et al. Epigenetic aspects of osteoporosis. Bulletin of the Russian Academy of Medical Sciences. 2015; 70 (5): 541–548. doi: 10.15690/vramn.v70.i5.1440 [in Russian].

20. Cheng H., Jiang W., Phillips F.M. et al. Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J. Bone Joint Surg. Am. 2003; 85-A: 1544–52.

21. Böttcher Y., Unbehauen H., Klöting N. et al. Adipose tissue expression and genetic variants of the bone morphogenetic protein receptor 1A gene (BMPR1A) are associated with human obesity. Diabetes. 2009; 58(9): 2119–2128. doi: 10.2337/db08-1458

22. Hayashi H., Ishisaki A., Suzuki M. et al. BMP-2 augments FGF-induced differentiation of PC12cells through upregulation of FGF receptor-1 expression. J Cell Sci. 2001; 114(Pt 7): 1387-95.

23. Chen D., Ji X., Harris M.A., Feng J.Q. et al. Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol. 1998; 142: 295–305.

24. Knight M.N., Hankenson K.D. Mesenchymal Stem Cells in Bone Regeneration. Adv Wound Care (New Rochelle).2013; 2: 306–316. doi: 10.1089/wound.2012.0420

25. Chen G., Deng C., Li Y.P. TGF-beta and BMP signaling in osteoblast differentiation and bone formation. Int. J. Biol. Sci. 2012; 8: 272–88. doi: 10.7150/ijbs.2929.

26. Jeong H.M., Jin Y.H., Kim Y.J. et al. Akt phosphorylates and regulates the function of Dlx5. Biochem Biophys Res Commun. 2011; 409: 681–6.

27. Daluiski A., Engstrand T., Bahamonde ME. et al. Bone morphogenetic protein-3 is a negative regulator of bone density. Nat Genet. 2001; 27: 84–8.

28. Haasters F., Docheva D., Gassner C. et al. Mesenchymal stem cells from osteoporotic patients reveal reduced migration and invasion upon stimulation with BMP-2 or BMP-7. Biochem. Biophys. Res. Commun. 2014; 452: 118–23. doi: 10.1016/j.bbrc.2014.08.055.

29. Takayanagi H., Kim S., Koga T. et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002; 3: 889–901.

30. Asagiri M., Sato K., Usami T. et al. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med. 2005; 202: 1261–1269. doi: 10.1084/jem.20051150

31. Kearns A.E., Khosla S., Kostenuik P.J. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008; 29: 155–92. doi: 10.1210/er.2007- 0014.

32. Hodge J.M., Collier F.M., Pavlos N.J. et al. M-CSF potently augments RANKL-induced resorption activation in mature human osteoclasts. PLoS One. 2011; 6:e21462. doi: 10.1371/journal.pone.0021462.

33. Martin T.J., Gooi J.H., Sims N.F. Molecular mechanisms in coupling of bone formation to resorption. Crit Rev Eukaryot Gene Expr. 2009; 19(1): 73-88.

34. Hou W.S., Li Z., Gordon R.E. 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.

35. Paiva K.B.S, Granjeiro J.M. Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair. Prog Mol Biol Transl Sci. 2017; 148: 203- 303. doi: 10.1016/bs.pmbts.2017.05.001.

36. Clarke B. Normal bone anatomy and physiology. Clin. J. Am. Soc. Nephrol. 2008; 3 Suppl 3:S131-9. doi: 10.2215/CJN.04151206.

37. Teitelbaum S.L. Osteoclasts: what do they do and how do they do it? Am. J. Pathol. 2007; 170(2): 427-435. doi: 10.2353/ajpath.2007.060834.

38. Boyce B.F., Xing L. The RANKL/RANK/OPG pathway. Curr Osteoporos Rep. 2007; 5: 98–104.

39. Zaiss M.M., Sarter K., Hess A. et al. Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation. Arthritis Rheum. 2010; 62(8): 2328–38. doi: 10.1002/art.27535.

40. Min H., Morony S., Sarosi I. et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J. Exp. Med. 2000; 192(4): 463–474.

41. Simonet W.S., Lacey D.L., Dunstan C.R. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997; 89: 309–19.

42. Rogers A., Eastell R. Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J. Clin. Endocrino.l Metab. 2005; 90(11): 6323–6331. doi: 10.1210/jc.2005-0794

43. Yuan F.L., Li X., Lu W.G. et al. Type 17 T-helper cells might be a promising therapeutic target for osteoporosis. Mol. Biol. Rep. 2012; 39(1): 771–774. doi: 10.1007/s11033-011-0797-z.

44. Kuo T.R., Chen C.H. Bone biomarker for the clinical assessment of osteoporosis: recent developments and future perspectives. Biomark. Res. 2017; 5: 18. doi: 10.1186/s40364-017-0097-4.

45. Смирнов А.В., Румянцев А.Ш. Строение и функции костной ткани в норме и при патологии. Сообщение II. Нефрология. 2015; 19(1): 8-17. Smirnov A.V., Rumyantsev A Sh. Bone tissue function and structure in normal and pathological condition. Message II. Nephrology. 2015; 19(1): 8-17 [in Russian].

46. Henriksen K., Neutzsky-Wulff A.V., Bonewald L.F. et al. Local communication on and within bone controls bone remodeling. Bone. 2009; 44(6): 1026-33. doi: 10.1016/j.bone.2009.03.671.

47. Zhao C., Irie N., Takada Y., Shimoda K. et al. Bidirectional ephrinB2- EphB4 signaling controls bone homeostasis. Cell Metab. 2006; 4(2): 111-21. doi: 10.1016/j.cmet.2006.05.012.

48. Pitulescu M.E., Adams R.H. Eph/ephrin molecules-a hub for signaling and endocytosis. Genes Dev. 2010; 24(22): 2480-92. doi: 10.1101/gad.1973910.

49. Davy A., Soriano P. Ephrin signaling in vivo: look both ways. Dev Dyn. 2005; 232(1): 1-10. doi: 10.1002/dvdy.20200.

50. Matsuo K., Otaki N. Bone cell interactions through Eph/ephrin Bone modeling, remodeling and associated diseases. Cell Adh Migr. 2012; 6(2): 148-56. doi: 10.4161/cam.20888.

51. Eriksen E.F., Gundersen H.J., Melsen F. et al. Reconstructionьof the formative site in iliac trabecular bone in 20 normal individuals employing a kinetic model for matrix and mineral apposition. Metab Bone Dis Relat Res. 1984; 5: 243–252.

52. Agerbaek M.O., Eriksen E.F., Kragstrup J. et al. A reconstruction of the remodelling cycle in normal human cortical iliac bone. Bone Miner. 1991; 12: 101–12.

53. Евстигнеева Л.П., Солодовников А.Г., Ершова О.Б. и др. Остеопороз. Диагностика, профилактика и лечение Москва, 2010, Клинические рекомендации (Второе издание, переработанное и дополненное). Evstigneeva L.P., Solodovnikov A.G., Ershova O.B. et al. Osteoporosis. Diagnosis, prevention and treatment Moscow, 2010, Clinical recommendations (Second edition, revised and supplemented) [in Russian].

54. Perez-Castrillon J.L., Olmos J.M., Nan D.N. et al. Polymorphisms of the WNT10B gene, bone mineral density, and fractures in postmenopausal women. Calcif Tissue Int. 2009; 85(2): 113–118. doi: 10.1007/s00223- 009-9256-4.

55. Chen J., Long F. Beta-catenin promotes bone formation and suppresses bone resorption in postnatal growing mice. J. Bone Miner. Res. 2013 May; 28(5):1160-9. doi: 10.1002/jbmr.1834.

56. Haasters F., Docheva D., Gassner C. et al. Mesenchymal stem cells from osteoporotic patients reveal reduced migration and invasion upon stimulation with BMP-2 or BMP-7. Biochem. Biophys. Res. Commun. 2014; 452(1): 118-23. doi: 10.1016/j.bbrc.2014.08.055.

57. Devlin R.D., Du Z., Pereira R.C., Kimble R.B. et al. Skeletal overexpression of noggin results in osteopenia and reduced bone formation. Endocrinology. 2003; 144(5): 1972-8. doi: 10.1210/en.2002-220918

58. Moffett S.P., Dillon K.A., Yerges L.M. et al. Identification and association analysis of single nucleotide polymorphisms in the human noggin (NOG) gene and osteoporosis phenotypes. Bone. 2009; 44(5): 999- 1002. doi: 10.1016/j.bone.2008.12.024.

59. Gazzerro E, Pereira R.C., Jorgetti V. et al. Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. Endocrinology. 2005; 146(2): 655-665. doi: 10.1210/en.2004-0766.

60. Cheung C., Lau K.S., Sham P.C., Tan K.C., Kung A.W. Genetic variants in GREM2 are associated with bone mineral density in a southern Chinese population. J. Clin. Endocrinol. Metab. 2013 Sep; 98(9): E1557-1561. doi: 10.1210/jc.2013-1983.

61. Mizuno A., Amizuka N., Irie K. et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem. Biophys. Res. Commun. 1998; 247: 610–5.

62. Mainini G., Incoronato M., Urso L. et al. Serum osteoprotegerin correlates with age and bone mass in postmenopausal, but not in fertile age women. Clin. Exp. Obstet. Gynecol. 2011; 38(4): 355-9.

63. Rifas L. Bone and cytokines: beyond IL-1, IL-6 and TNF-alpha. Calcif Tissue Int. 1999; 64: 1–7.

64. Yuan F.L., Li X., Lu W.G. et al. Type 17 T-helper cells might be a promising therapeutic target for osteoporosis. Mol. Biol. Rep. 2012; 39(1): 771-4. doi: 10.1007/s11033-011-0797-z.

65. Sato K., Suematsu A., Okamoto K. et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 2006; 203(12): 2673-82. doi: 10.1084/jem.20061775.

66. Tyagi A.M., Srivastava K., Mansoori M.N. et al. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS One. 2012; 7(9): e44552. doi: 10.1371/journal.pone.0044552.

67. Zhao R. Immune regulation of bone loss by Th17 cells in oestrogendeficient osteoporosis. Eur. J. Clin. Invest. 2013 Nov; 43(11): 1195-202. doi: 10.1111/eci.12158.

68. Eastell R., Hannon R.A. Biomarkers of bone health and osteoporosis risk. Proc. Nutr. Soc. 2008; 67(2): 157-62. doi: 10.1017/S002966510800699X.

69. Wheater G., Elshahaly M., Tuck S.P. et al. The clinical utility of bone marker measurements in osteoporosis. J. Transl. Med. 2013 Aug 29; 11: 201. doi: 10.1186/1479-5876-11-201.