Роль мембранных рецепторов, ассоциированных с G-белком, в патогенезе остеопороза

Остеопороз — это хроническое заболевание, характеризующееся патологическим изменением костной ткани, чрезмерной хрупкостью и снижением прочности костей в результате преобладания процессов костной резорбции над процессом костеобразования. Данное заболевание проявляется в виде низкотравматических переломов, возникающих при падении с высоты своего роста или при незначительной физической нагрузке. Одним из осложнений остеопороза является перелом шейки бедренной кости, который приводит к высокой летальности, инвалидизации и большим затратам на лечение. Социальная значимость остеопороза определяется его последствиями — переломами тел позвонков и костей периферического скелета, обусловливающими высокий уровень нетрудоспособности, включая инвалидность и смертность. Важно отметить, что у женщин на фоне прекращения менструального цикла развивается постменопаузальный остеопороз. В данном обзоре рассматривается роль мембранных рецепторов, ассоциированных с G-белком (семейство GPCR), в патогенезе данного заболевания и перспективы поиска мишеней среди этих рецепторов для диагностики и лечения остеопороза. Было показано, что изменения генов, кодирующих GPCR, приводят к нарушению ремоделирования костной ткани. Одной из актуальных задач исследования функций белков семейства GPCR является поиск маркеров предрасположенности к дисфункции костной ткани для оптимизации ранней диагностики остеопороза. Исследования на модели остеобластов, дифференцированных из индуцированных плюрипотентных стволовых клеток человека (ИПСКч), полученных от пациентов с остеопорозом, ассоциированным с мутациями в генах семейства GPCR, позволят глубже понять молекулярную природу остеопороза и выявить новые таргетные молекулы для разработки эффективных методов лечения.

1. Siris ES, Adler R, Bilezikian J et al. The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 2014; 25(5):1439-1443. DOI: 10.1007/s00198-014-2655-z.

2. Siris ES, Boonen S, Mitchell PJ et al. What’s in a name? What constitutes the clinical diagnosis of osteoporosis? Osteoporos Int. 2012; 23(8):2093-2097. DOI: 10.1007/s00198-012-1991-0.

3. Belaya ZE, Belova KYu, Biryukova EV, et al. Federal clinical guidelines for diagnosis, treatment and prevention of osteoporosis. Osteoporosis and Bone Diseases. 2021; 24(2):4-47. In Russian [ Белая Ж.Е., Белова К.Ю., Бирюкова Е.В., и др. Федеральные клинические рекомендации по диагностике, лечению и профилактике остеопороза. Остеопороз и остеопатии. 2021;24(2):4- 47]. DOI: 10.14341/osteo12930

4. Camacho PM, Petak SM, Binkley N, et al. American association of clinical endocrinologists and American college of endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis — 2016. Endocr Pract. 2016; 22(Suppl 4):1- 42. DOI: 10.4158/EP161435.GL.

5. Kanis JA, Cooper C, Rizzoli R, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2019; 30(1):3- 44. DOI: 10.1007/s00198-018-4704-5.

6. Willers C, Norton N, Harvey NC et al. Osteoporosis in Europe: a compendium of country-specific reports. Arch Osteoporos. 2022;17(1):23. DOI: 10.1007/s11657-021-00969-8.

7. Kanis JA, Norton N, Harvey NC et al. SCOPE 2021: a new scorecard for osteoporosis in Europe. Arch Osteoporos. 2021; 16(1):82. DOI: 10.1007/s11657-020-00871-9.

8. Lesnyak O.M. International research projects in the osteoporosis: common efforts, one goal. Russian Family Doctor. 2016; 20(2):43-46. In Russian [Лесняк О.М. Международные научные проекты в области остеопороза: общие усилия, одна цель. Российский семейный врач. 2016; 20(2):43-46]. DOI: 10.17816/RFD2016243-46

9. Maeda K, Takahashi N, Kobayashi Y. Roles of Wnt signals in bone resorption during physiological and pathological states. J Mol Med (Berl). 2013; 91(1):15-23. DOI: 10.1007/s00109-012-0974-0.

10. Boyce BF, Xing L. The RANKL/RANK/OPG pathway. Curr Osteoporos Rep. 2007;5(3):98-104. DOI: 10.1007/s11914-007-0024-y.

11. Chen X, Wang Z, Duan N et al. Osteoblastosteoclast interactions. Connect Tissue Res. 2018; 59(2):99- 107. DOI: 10.1080/03008207.2017.1290085.

12. Zhang YY, Liu PY, Lu Y et al. Tests of linkage and association of PTH/PTHrP receptor type 1 gene with bone mineral density and height in Caucasians. J Bone Miner Metab. 2006; 24(1):36-41. DOI: 10.1007/s00774-005-0643-2.

13. Lee SH, Kim TS, Choi Y et al. Osteoimmunology: cytokines and the skeletal system. BMB Rep. 2008; 41(7):495-510. DOI: 10.5483/bmbrep.2008.41.7.495

14. Gao Y, Grassi F, Ryan MR et al. IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest. 2007; 117(1):122-132. DOI: 10.1172/JCI30074

15. Lencel P, Magne D. Inflammaging: the driving force in osteoporosis? Med Hypotheses. 2011; 76(3):317- 321. DOI: 10.1016/j.mehy.2010.09.023

16. Bondeson J, Blom AB, Wainwright S et al. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 2010; 62(3):647-657. DOI: 10.1002/art.27290.

17. Pino AM, Ríos S, Astudillo P et al. Concentration of adipogenic and proinflammatory cytokines in the bone marrow supernatant fluid of osteoporotic women. J Bone Miner Res. 2010; 25(3):492-498. DOI: 10.1359/jbmr.090802

18. Pacifici R, Brown C, Puscheck E et al. Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci U S A. 1991; 88(12):5134-5138. DOI: 10.1073/pnas.88.12.5134

19. Pfeilschifter J, Köditz R, Pfohl M et al. Changes in proinflammatory cytokine activity after menopause. Endocr Rev. 2002; 23(1):90-119. DOI: 10.1210/edrv.23.1.0456

20. Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest. 2006; 116(5):1186-1194. DOI: 10.1172/JCI28550.

21. Cauley JA, Danielson ME, Boudreau RM et al. Inflammatory markers and incident fracture risk in older men and women: the Health Aging and Body Composition Study. J Bone Miner Res. 2007; 22(7):1088-1095. DOI: 10.1359/jbmr.070409

22. Charatcharoenwitthaya N, Khosla S, Atkinson EJ et al. Effect of blockade of TNF-alpha and interleukin-1 action on bone resorption in early postmenopausal women. J Bone Miner Res. 2007; 22(5):724-729. DOI: 10.1359/jbmr.070207.

23. Takayanagi H, Kim S, Matsuo K et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature. 2002; 416(6882):744- 749. DOI: 10.1038/416744a.

24. Takayanagi H, Ogasawara K, Hida S et al. T-cellmediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000; 408(6812):600-605. DOI: 10.1038/35046102

25. Cenci S, Toraldo G, Weitzmann MN et al. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc Natl Acad Sci U S A. 2003; 100(18):10405-10410. DOI: 10.1073/pnas.1533207100.

26. Janssens K, ten Dijke P, Janssens S et al. Transforming growth factor-beta1 to the bone. Endocr Rev. 2005; 26(6):743-774. DOI: 10.1210/er.2004-0001

27. Kudo O, Fujikawa Y, Itonaga I et al. Proinflammatory cytokine (TNFalpha/IL-1alpha) induction of human osteoclast formation. J Pathol. 2002; 198(2):220- 227. DOI: 10.1002/path.1190

28. Kudo O, Sabokbar A, Pocock A et al. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone. 2003; 32(1):1-7. DOI: 10.1016/s8756-3282(02)00915-8

29. Yoshitake F, Itoh S, Narita H, et al. Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. J Biol Chem. 2008; 283(17):11535-11540. DOI: 10.1074/jbc.M607999200

30. Theoleyre S, Wittrant Y, Tat SK, et al. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 2004; 15(6):457-475. DOI: 10.1016/j.cytogfr.2004.06.004

31. Fuller K, Murphy C, Kirstein B, et al. TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology. 2002; 143(3):1108-1118. DOI: 10.1210/endo.143.3.8701

32. Itonaga I, Sabokbar A, Sun SG, et al. Transforming growth factor-beta induces osteoclast formation in the absence of RANKL. Bone. 2004; 34(1):57-64. DOI: 10.1016/j.bone.2003.08.008.

33. Kobayashi K, Takahashi N, Jimi E, et al. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med. 2000; 191(2):275-286. DOI: 10.1084/jem.191.2.275

34. Baim S, Binkley N, Bilezikian JP, et al. Official positions of the international society for clinical densitometry and executive summary of the 2007 ISCD position development conference. J Clin Densitom. 2008; 11(1):75-91. DOI: 10.1016/j.jocd.2007.12.007.

35. Watts NB, Leslie WD, Foldes AJ, et al. International society for clinical densitometry position development conference: task force on normative databases. J Clin Densitom. 2013; 16(4):472-481. DOI: 10.1016/j.jocd.2013.08.001

36. Lesniak OM. Osteoporosis audit in the Russian Federation. Profilakticheskaya Meditsina. 2011; 14(2):7- 10. In Russian [Лесняк О.М. Аудит состояния проблемы остеопороза в Российской Федерации. Профилактическая медицина. 2011;14(2):7-10].

37. Nikitinskaya OA, Toroptsova NV. Assessment of 10-year probability of osteoporotic fractures with the russian model of FRAX® in a population-based sample 5 regions of Russia. Meditsinskiy sovet=Medical Council. 2017; (1S):103- 107. In Russian [Никитинская О.А., Торопцова Н.В. Оценка 10-летней вероятности остеопоротических переломов с помощью российской модели FRAX® в популяционных выборках 5 регионов России. Медицинский совет. 2017; (1S):103-107]. DOI: 10.21518/2079-701X-2017-0-103-107

38. Tu KN, Lie JD, Wan CKV, et al. Osteoporosis: A Review of Treatment Options. P T. 2018; 43(2):92-104.

39. Nancollas GH, Tang R., Gulde S. et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006; 38(5):617– 627. DOI: 10.1016/j.bone.2005.05.003

40. Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des. 2003; 9(32):2643-2658. DOI: 10.2174/1381612033453640.

41. Wu FY, Liu CS, Liao LN et al. Vitamin D receptor variability and physical activity are jointly associated with low handgrip strength and osteoporosis in communitydwelling elderly people in Taiwan: the Taichung Community Health Study for Elders (TCHS-E). Osteoporos Int. 2014; 25(7):1917-1929. DOI: 10.1007/s00198-014-2691-8.

42. Luo L, Xia W, Nie M et al. Association of ESR1 and C6orf97 gene polymorphism with osteoporosis in postmenopausal women. Mol Biol Rep. 2014; 41(5):3235- 3243. DOI: 10.1007/s11033-014-3186-6.

43. Tural S, Alayli G, Kara N et al. Association between osteoporosis and polymorphisms of the IL-10 and TGF-beta genes in Turkish postmenopausal women. Hum Immunol. 2013; 74(9):1179-1183. DOI: 10.1016/j.humimm.2013.03.005.

44. Tural S, Kara N, Alayli G et al. Association between osteoporosis and polymorphisms of the bone Gla protein, estrogen receptor 1, collagen 1-A1 and calcitonin receptor genes in Turkish postmenopausal women. Gene. 2013; 515(1):167-172. DOI: 10.1016/j.gene.2012.10.041

45. Schöneberg T, Schulz A, Biebermann H et al. Mutant G-protein-coupled receptors as a cause of human diseases. Pharmacol Ther. 2004; 104(3):173-206. DOI: 10.1016/j.pharmthera.2004.08.008.

46. Luo J, Sun P, Siwko S et al. The role of GPCRs in bone diseases and dysfunctions. Bone Res. 2019; 7:19. DOI: 10.1038/s41413-019-0059-6.

47. Schöneberg T, Liebscher I. Mutations in G Protein-Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches. Pharmacol Rev. 2021; 73(1):89-119. DOI: 10.1124/pharmrev.120.000011

48. Stoy H, Gurevich VV. How genetic errors in GPCRs affect their function: Possible therapeutic strategies. Genes Dis. 2015; 2(2):108-132. DOI: 10.1016/j.gendis.2015.02.005

49. Chen Q, Iverson TM, Gurevich VV. Structural Basis of Arrestin-Dependent Signal Transduction. Trends Biochem Sci. 2018; 43(6):412-423. DOI: 10.1016/j.tibs.2018.03.005.

50. Schöneberg J, Lee IH, Iwasa JH et al. Reversetopology membrane scission by the ESCRT proteins. Nat Rev Mol Cell Biol. 2017; 18(1):5-17. DOI: 10.1038/nrm.2016.121.

51. Dvorak MM, Siddiqua A, Ward DT, et al. Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc Natl Acad Sci USA. 2004; 101(14):5140–5145. DOI: 10.1073/pnas.0306141101

52. Yano S, Sugimoto T, Tsukamoto T, et al. Association of decreased calcium-sensing receptor expression with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney Int. 2000;58(5):1980-1986. DOI: 10.1111/j.1523-1755.2000.00370.x.

53. Takeyama S, Yoshimura Y, Shirai Y, et al. Low calcium environment effects osteoprotegerin ligand/ osteoclast differentiation factor. Biochem Biophys Res Commun. 2000; 276(2):524–529. DOI: 10.1006/bbrc.2000.3498

54. Välimäki S, Farnebo F, Forsberg L et al. Heterogeneous expression of receptor mRNAs in parathyroid glands of secondary hyperparathyroidism. Kidney Int. 2001; 60(5):1666-1675. DOI: 10.1046/j.1523-1755.2001.00986.x.

55. Cheshmedzhieva D, Ilieva S, Permyakov EA et al. Ca2+/Sr2+ selectivity in calcium-sensing receptor (CaSR): implications for strontium’s anti-osteoporosis effect. Biomolecules. 2021; 11(11):1576. DOI: 10.3390/biom11111576

56. Chang W, Tu C, Chen TH et al. The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci Signal. 2008; 1(35):ra1. DOI: 10.1126/scisignal.1159945.

57. Hendy GN, Guarnieri V, Canaff L. Calciumsensing receptor and associated diseases. Prog Mol Biol Transl Sci. 2009; 89:31-95. DOI: 10.1016/S1877-1173(09)89003-0.

58. Menko FH, Bijvoet OL, Fronen JL, et al. Familial benign hypercalcaemia. Study of a large family. Q J Med. 1983; 52(206):120-140.

59. Fitzpatrick LA, Dabrowski CE, Cicconetti G, et al. Ronacaleret, a calcium-sensing receptor antagonist, increases trabecular but not cortical bone in postmenopausal women. J Bone Miner Res. 2012; 27(2):255-262. DOI: 10.1002/jbmr.554

60. Halse J, Greenspan S, Cosman F, et al. A phase 2, randomized, placebo-controlled, dose-ranging study of the calcium-sensing receptor antagonist MK-5442 in the treatment of postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2014; 99(11):E2207-2215. DOI: 10.1210/jc.2013-4009

61. Goltzman D, Hendy GN. The calcium-sensing receptor in bone--mechanistic and therapeutic insights. Nat Rev Endocrinol. 2015; 11(5):298-307. DOI: 10.1038/nrendo.2015.30

62. Di Nisio A, Rocca MS, Ghezzi M et al. Calciumsensing receptor polymorphisms increase the risk of osteoporosis in ageing males. Endocrine. 2018; 61(2):349- 352. DOI: 10.1007/s12020-017-1429-8.

63. Gat-Yablonski G, Ben-Ari T, Shtaif B et al. Leptin reverses the inhibitory effect of caloric restriction on longitudinal growth. Endocrinology. 2004; 145(1):343-350. DOI: 10.1210/en.2003-0910.

64. Welt CK, Chan JL, Bullen J et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004; 351(10):987-997. DOI: 10.1056/NEJMoa040388

65. Lee HJ, Kim H, Ku SY et al. Association between polymorphisms in leptin, leptin receptor, and β-adrenergic receptor genes and bone mineral density in postmenopausal Korean women. Menopause. 2014; 21(1):67-73. DOI: 10.1097/GME.0b013e31829366ed

66. Akune T, Ohba S, Kamekura S et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest. 2004; 113(6):846-855. DOI: 10.1172/JCI19900

67. Quennell JH, Mulligan AC, Tups A et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2009; 150(6):2805-2812. DOI: 10.1210/en.2008-1693

68. Loram LC, Culp ME, Connolly-Strong EC et al. Melanocortin peptides: potential targets in systemic lupus erythematosus. Inflammation. 2015; 38(1):260-271. DOI: 10.1007/s10753-014-0029-5

69. Farooqi IS, Yeo GS, Keogh JM et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest. 2000; 106(2):271-279. DOI: 10.1172/JCI9397

70. Lin L, Conway GS, Hill NR et al. A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as constitutional delay of growth and puberty with subsequent borderline oligospermia. J Clin Endocrinol Metab. 2006; 91(12):5117-5121. DOI: 10.1210/jc.2006-0807

71. Man GC, Wong JH, Wang WW et al. Abnormal melatonin receptor 1B expression in osteoblasts from girls with adolescent idiopathic scoliosis. J Pineal Res. 2011; 50(4):395-402. DOI: 10.1111/j.1600-079X.2011.00857.x

72. Li Y, Zhou J, Wu Y et al. Association of osteoporosis with genetic variants of circadian genes in Chinese geriatrics. Osteoporos Int. 2016; 27(4):1485-1492. DOI: 10.1007/s00198-015-3391-8

73. De Petrocellis L, Cascio MG, Di Marzo V. The endocannabinoid system: a general view and latest additions. Br J Pharmacol. 2004; 141(5):765-774. DOI: 10.1038/sj.bjp.0705666.

74. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003; 4(11):873-884. DOI: 10.1038/nrn1247

75. Idris AI, Ralston SH. Role of cannabinoids in the regulation of bone remodeling. Front Endocrinol (Lausanne). 2012; 3:136. DOI: 10.3389/fendo.2012.00136

76. Bab I, Zimmer A. Cannabinoid receptors and the regulation of bone mass. Br J Pharmacol. 2008; 153(2):182- 188. DOI: 10.1038/sj.bjp.0707593

77. Bab I, Ofek O, Tam J et al. Endocannabinoids and the regulation of bone metabolism. J Neuroendocrinol. 2008; 20 Suppl 1:69-74. DOI: 10.1111/j.1365-2826.2008.01675.x

78. Idris AI, van ‘t Hof RJ, Greig IR et al. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med. 2005; 11(7):774-779. DOI: 10.1038/nm1255

79. Sophocleous A, Landao-Bassonga E, Van’t Hof RJ et al. The type 2 cannabinoid receptor regulates bone mass and ovariectomy-induced bone loss by affecting osteoblast differentiation and bone formation. Endocrinology. 2011; 152(6):2141-2149. DOI: 10.1210/en.2010-0930

80. Qian H, Zhao Y, Peng Y et al. Activation of cannabinoid receptor CB2 regulates osteogenic and osteoclastogenic gene expression in human periodontal ligament cells. J Periodontal Res. 2010; 45(4):504-511. DOI: 10.1111/j.1600-0765.2009.01265.x

81. Napimoga MH, Benatti BB, Lima FO et al. Cannabidiol decreases bone resorption by inhibiting RANK/ RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats. Int Immunopharmacol. 2009; 9(2):216-222. DOI: 10.1016/j.intimp.2008.11.010

82. Geng DC, Xu YZ, Yang HL et al. Cannabinoid receptor-2 selective antagonist negatively regulates receptor activator of nuclear factor JB ligand mediated osteoclastogenesis. Chin Med J (Engl). 2011; 124(4):586-590.

83. Wang B, Lian K, Li J et al. Restoration of osteogenic differentiation by overexpression of cannabinoid receptor 2 in bone marrow mesenchymal stem cells isolated from osteoporotic patients. Exp Ther Med. 2018; 15(1):357- 364. DOI: 10.3892/etm.2017.5369

84. Woo JH, Kim H, Kim JH et al. Cannabinoid receptor gene polymorphisms and bone mineral density in Korean postmenopausal women. Menopause. 2015; 22(5):512-519. DOI: 10.1097/GME.0000000000000339

85. Sophocleous A, Marino S, Kabir D et al. Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition. Aging Cell. 2017; 16(5):1051-1061. DOI: 10.1111/acel.12638

86. Freemantle N, Holmes J, Hockey A et al. How strong is the association between abdominal obesity and the incidence of type 2 diabetes? Int J Clin Pract. 2008; 62(9):1391-1396. DOI: 10.1111/j.1742-1241.2008.01805.x

87. Styrkarsdottir U, Thorleifsson G, Sulem P et al. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature. 2013; 497(7450):517–520. DOI: 10.1038/nature12124.

88. Shi SQ, Li SS, Zhang XY et al. LGR4 gene polymorphisms are associated with bone and obesity phenotypes in chinese female nuclear families. Front Endocrinol (Lausanne). 2021; 12:656077. DOI: 10.3389/fendo.2021.656077

89. Liu RD, Chen RX, Li WR et al. The Glu727 allele of thyroid stimulating hormone receptor gene is associated with osteoporosis. N Am J Med Sci. 2012; 4(7):300-304. DOI: 10.4103/1947-2714.98588

90. van der Deure WM, Uitterlinden AG, Hofman A et al. Effects of serum TSH and FT4 levels and the TSHR-Asp727Glu polymorphism on bone: the Rotterdam Study. Clin Endocrinol (Oxf). 2008; 68(2):175-181. DOI: 10.1111/j.1365-2265.2007.03016.x.

91. Rendina D, Gianfrancesco F, De Filippo G et al. FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women. Eur J Endocrinol. 2010; 163(1):165-172. DOI: 10.1530/EJE-10-0043

92. Van Coillie E, Van Damme J, Opdenakker G. The MCP/eotaxin subfamily of CC chemokines. Cytokine Growth Factor Rev. 1999; 10(1):61-86. DOI: 10.1016/s1359-6101(99)00005-2

93. Yu X, Graves DT. Fibroblasts, mononuclear phagocytes, and endothelial cells express monocyte chemoattractant protein-1 (MCP-1) in inflamed human gingiva. J Periodontol. 1995; 66(1):80-88. DOI: 10.1902/jop.1995.66.1.80

94. Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997; 89(2):309-319. DOI: 10.1016/s0092-8674(00)80209-3

95. Rovin BH, Lu L, Saxena R. A novel polymorphism in the MCP-1 gene regulatory region that influences MCP- 1 expression. Biochem Biophys Res Commun. 1999; 259(2):344-348. DOI: 10.1006/bbrc.1999.0796

96. Rollins BJ. Chemokines. Blood. 1997; 90:909– 928.

97. Eraltan H, Cacina C, Kahraman OT et al. MCP-1 and CCR2 gene variants and the risk for osteoporosis and osteopenia. Genetic Testing and Molecular Biomarkers. 2012; 16(4):229–233. DOI: 10.1089/gtmb.2011.0216

98. Schlüter KD. PTH and PTHrP: Similar Structures but Different Functions. News Physiol Sci. 1999; 14:243- 249. DOI: 10.1152/physiologyonline.1999

99. Jans DA, Thomas RJ, Gillespie MT. Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles. Vitam Horm. 2003; 66:345-384. DOI: 10.1016/s0083-6729(03)01010-0

100. Strewler GJ. The physiology of parathyroid hormone-related protein. N Engl J Med. 2000; 342(3):177- 185. DOI: 10.1056/NEJM200001203420306

101. Fiaschi-Taesch NM, Stewart AF. Minireview: parathyroid hormone-related protein as an intracrine factor- -trafficking mechanisms and functional consequences. Endocrinology. 2003; 144(2):407-411. DOI: 10.1210/en.2002-220818

102. Weiss S, Hennig T, Bock R et al. Impact of growth factors and PTHrP on early and late chondrogenic differentiation of human mesenchymal stem cells. J Cell Physiol. 2010; 223(1):84-93. DOI: 10.1002/jcp.22013

103. Miao D, He B, Karaplis AC et al. Parathyroid hormone is essential for normal fetal bone formation. J Clin Invest. 2002; 109(9):1173-1182. DOI: 10.1172/JCI14817

104. Boileau G, Tenenhouse HS, Desgroseillers L et al. Characterization of PHEX endopeptidase catalytic activity: identification of parathyroid-hormone-related peptide107-139 as a substrate and osteocalcin, PPi and phosphate as inhibitors. Biochem J. 2001; 355(Pt 3):707- 713. DOI: 10.1042/bj3550707

105. Bisello A, Horwitz MJ, Stewart AF. Parathyroid hormone-related protein: an essential physiological regulator of adult bone mass. Endocrinology. 2004; 145(8):3551- 3553. DOI: 10.1210/en.2004-0509

106. Horwitz MJ, Tedesco MB, Garcia-Ocaña A et al. Parathyroid hormone-related protein for the treatment of postmenopausal osteoporosis: defining the maximal tolerable dose. J Clin Endocrinol Metab. 2010; 95(3):1279- 1287. DOI: 10.1210/jc.2009-0233

107. Ahlström M, Pekkinen M, Lamberg-Allardt C. Dexamethasone downregulates the expression of parathyroid hormone-related protein (PTHrP) in mesenchymal stem cells. Steroids. 2009; 74(2):277-282. DOI: 10.1016/j.steroids.2008.12.002

108. Scillitani A, Jang C, Wong BY et al. A functional polymorphism in the PTHR1 promoter region is associated with adult height and BMD measured at the femoral neck in a large cohort of young caucasian women. Hum Genet. 2006; 119(4):416-421. DOI: 10.1007/s00439-006-0155-8

109. Lee HJ, Kim SY, Kim GS et al. Fracture, bone mineral density, and the effects of calcitonin receptor gene in postmenopausal Koreans. Osteoporos Int. 2010;21(8):1351- 1360. DOI: 10.1007/s00198-009-1106-8

110. Aguiar-Oliveira MH, Cardoso-Filho MA, Pereira RM et al. Older individuals heterozygous for a growth hormone-releasing hormone receptor gene mutation are shorter than normal subjects. J Hum Genet. 2015; 60(6):335- 338. DOI: 10.1038/jhg.2015.25

111. Faivre E, Gault VA, Thorens B et al. Glucosedependent insulinotropic polypeptide receptor knockout mice are impaired in learning, synaptic plasticity, and neurogenesis. J Neurophysiol. 2011; 105(4):1574-1580. DOI: 10.1152/jn.00866.2010

112. Torekov SS, Harsløf T, Rejnmark L et al. A functional amino acid substitution in the glucose-dependent insulinotropic polypeptide receptor (GIPR) gene is associated with lower bone mineral density and increased fracture risk. J Clin Endocrinol Metab. 2014; 99(4):E729- 733. DOI: 10.1210/jc.2013-3766

113. Mórocz M, Czibula A, Grózer ZB et al. Association study of BMP4, IL6, Leptin, MMP3, and MTNR1B gene promoter polymorphisms and adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2011; 36(2):E123-130. DOI: 10.1097/BRS.0b013e318a511b0e

114. Kalinkovich A, Livshits G. Biased and allosteric modulation of bone cell-expressing G protein-coupled receptors as a novel approach to osteoporosis therapy. Pharmacol Res. 2021; 171:105794. DOI: 10.1016/j.phrs.2021.105794

115. Ricci F, Vacchetti M, Brusa C et al. New pharmacotherapies for genetic neuromuscular disorders: opportunities and challenges. Expert Rev Clin Pharmacol. 2019; 12(8):757-770. DOI: 10.1080/17512433.2019.1634543

116. Bannuru RR, Osani MC, Vaysbrot EE et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019; 27(11):1578-1589. DOI: 10.1016/j.joca.2019.06.011

117. Thysen S, Luyten FP, Lories RJ. Targets, models and challenges in osteoarthritis research. Dis Model Mech. 2015; 8(1):17-30. DOI: 10.1242/dmm.016881

118. Singh VK, Kalsan M, Kumar N et al. Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol. 2015; 3:2. DOI: 10.3389/fcell.2015.00002

119. Desnuelle C, Dib M, Garrel C et al. A doubleblind, placebo-controlled randomized clinical trial of alphatocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001; 2(1):9-18. DOI: 10.1080/146608201300079364

120. Shefner JM, Cudkowicz ME, Schoenfeld D et al. A clinical trial of creatine in ALS. Neurology. 2004; 63(9):1656-1661. DOI: 10.1212/01.wnl.0000142992.81995.f0

121. Li WJ, Jiao H, Walczak BE. Emerging opportunities for induced pluripotent stem cells in orthopaedics. J Orthop Translat. 2019; 17:73-81. DOI: 10.1016/j.jot.2019.03.001

122. Park IH, Arora N, Huo H et al. Disease-specific induced pluripotent stem cells. Cell. 2008; 134(5):877-886. DOI: 10.1016/j.cell.2008.07.041

123. Csobonyeiova M, Polak S, Zamborsky R et al. iPS cell technologies and their prospect for bone regeneration and disease modeling: A mini review. J Adv Res. 2017; 8(4):321-327. DOI: 10.1016/j.jare.2017.02.004

124. Kao CL, Tai LK, Chiou SH et al. Resveratrol promotes osteogenic differentiation and protects against dexamethasone damage in murine induced pluripotent stem cells. Stem Cells Dev. 2010; 19(2):247-258. DOI: 10.1089/scd.2009.0186

125. Ardeshirylajimi A, Soleimani M. Enhanced growth and osteogenic di_erentiation of induced pluripotent stem cells by extremely low-frequency electromagnetic field. Cell Mol Biol. 2015; 61: 36–41.

126. Sanjurjo-Rodríguez C, Castro-Viñuelas R, Piñeiro-Ramil M et al. Versatility of Induced Pluripotent Stem Cells (iPSCs) for Improving the Knowledge on Musculoskeletal Diseases. Int J Mol Sci. 2020; 21(17):6124. DOI: 10.3390/ijms21176124

127. Ou M, Li C, Tang D et al. Genotyping, generation and proteomic profiling of the first human autosomal dominant osteopetrosis type II-specific induced pluripotent stem cells. Stem Cell Res Ther. 2019; 10(1):251. DOI: 10.1186/s13287-019-1369-8

128. Kawai S, Yoshitomi H, Sunaga J et al. In vitro bone-like nodules generated from patient-derived iPSCs recapitulate pathological bone phenotypes. Nat Biomed Eng. 2019; 3(7):558-570. DOI: 10.1038/s41551-019-0410-7