The Role of Osteoprotegerin in Vascular Calcification and Bone Metabolism: The Basis for Developing New Therapeutics

  • Luc RochetteEmail author
  • Alexandre Meloux
  • Eve Rigal
  • Marianne Zeller
  • Gabriel Malka
  • Yves Cottin
  • Catherine Vergely


Osteoporosis (OP) and cardiovascular diseases (CVD) are both important causes of mortality and morbidity in aging patients. There are common mechanisms underlying the regulation of bone remodeling and the development of smooth muscle calcification; a temporal relationship exists between osteoporosis and the imbalance of mineral metabolism in the vessels. Vascular calcification appears regulated by mechanisms that include both inductive and inhibitory processes. Multiple factors are implicated in both bone and vascular metabolism. Among these factors, the superfamily of tumor necrosis factor (TNF) receptors including osteoprotegerin (OPG) and its ligands has been established. OPG is a soluble decoy receptor for receptor activator of nuclear factor-kB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG binds to RANKL and TRAIL, and inhibits the association with their receptors, which have been labeled as the receptor activator of NF-kB (RANK). Sustained release of OPG from vascular endothelial cells (ECs) has been demonstrated in response to inflammatory proteins and cytokines, suggesting that OPG/RANKL/RANK system plays a modulatory role in vascular injury and inflammation. For the development of potential therapeutic strategies targeting vascular calcification, critical consideration of the implications for bone metabolism must be taken into account to prevent potentially detrimental effects to bone metabolism.


Osteoprotegerin Calcium Vascular Bone 



The authors wish to thank Philip Bastable for English assistance.


This work was supported by grants from French Ministry of Research, INSERM (Institut national de la santé et de la recherche médicale) and from the Regional Council of Burgundy (Conseil Régional de Bourgogne), FEDER, and Association de Cardiologie de Bourgogne. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Compliance with Ethical Standards

Conflict of interest

Luc Rochette, Alexandre Meloux, Eve Rigal, Marianne Zeller, Gabriel Malka, Yves Cottin, and Catherine Vergely declare that they did not receive funding from any sources and had no conflicts of interest.


  1. 1.
    Compston JE, McClung MR, Leslie WD (2019) Osteoporosis. Lancet 393:364–376CrossRefGoogle Scholar
  2. 2.
    Walsh MC, Choi Y (2014) Biology of the RANKL-RANK-OPG system in immunity, bone, and beyond. Front Immunol 5:511CrossRefGoogle Scholar
  3. 3.
    Rochette L, Meloux A, Rigal E, Zeller M, Cottin Y, Vergely C (2018) The role of osteoprotegerin in the crosstalk between vessels and bone: its potential utility as a marker of cardiometabolic diseases. Pharmacol Ther 182:115–132CrossRefGoogle Scholar
  4. 4.
    Barbu CG, Arsene AL, Florea S, Albu A, Sirbu A, Martin S, Nicolae AC, Burcea-Dragomiroiu GTA, Popa DE, Velescu BS, Dumitrescu IB, Mitrea N, Draganescu D, Lupuliasa D, Spandidos DA, Tsatsakis AM, Dragoi CM, Fica S (2017) Cardiovascular risk assessment in osteoporotic patients using osteoprotegerin as a reliable predictive biochemical marker. Mol Med Rep 16:6059–6067CrossRefGoogle Scholar
  5. 5.
    Faggiano P, Dasseni N, Gaibazzi N, Rossi A, Henein M, Pressman G (2019) Cardiac calcification as a marker of subclinical atherosclerosis and predictor of cardiovascular events: a review of the evidence. Eur J Prev Cardiol. Google Scholar
  6. 6.
    Chung CP, Solus JF, Oeser A, Li C, Raggi P, Smith JR, Stein CM (2015) A variant in the osteoprotegerin gene is associated with coronary atherosclerosis in patients with rheumatoid arthritis: results from a candidate gene study. Int J Mol Sci 16:3885–3894CrossRefGoogle Scholar
  7. 7.
    Feng X (2005) RANKing intracellular signaling in osteoclasts. IUBMB Life 57:389–395CrossRefGoogle Scholar
  8. 8.
    Martin-Ventura JL, Munoz-Garcia B, Egido J, Blanco-Colio LM (2007) Trail and vascular injury. Front Biosci 12:3656–3667CrossRefGoogle Scholar
  9. 9.
    Harper E, Forde H, Davenport C, Rochfort KD, Smith D, Cummins PM (2016) Vascular calcification in type-2 diabetes and cardiovascular disease: integrative roles for OPG, RANKL and TRAIL. Vasc Pharmacol 82:30–40CrossRefGoogle Scholar
  10. 10.
    Ikeda T, Kasai M, Utsuyama M, Hirokawa K (2001) Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus. Endocrinology 142:1419–1426CrossRefGoogle Scholar
  11. 11.
    Forde H, Harper E, Davenport C, Rochfort KD, Wallace R, Murphy RP, Smith D, Cummins PM (2016) The beneficial pleiotropic effects of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) within the vasculature: a review of the evidence. Atherosclerosis 247:87–96CrossRefGoogle Scholar
  12. 12.
    D’Auria F, Centurione L, Centurione MA, Angelini A, Di Pietro R (2015) Tumor necrosis factor related apoptosis inducing ligand (Trail) in endothelial response to biomechanical and biochemical stresses in arteries. J Cell Biochem 116:2427–2434CrossRefGoogle Scholar
  13. 13.
    Cunha DA, Cito M, Carlsson PO, Vanderwinden JM, Molkentin JD, Bugliani M, Marchetti P, Eizirik DL, Cnop M (2016) Thrombospondin 1 protects pancreatic beta-cells from lipotoxicity via the PERK-NRF2 pathway. Cell Death Differ 23:1995–2006CrossRefGoogle Scholar
  14. 14.
    Milanova V, Ivanovska N, Dimitrova P (2014) TLR2 elicits IL-17-mediated RANKL expression, IL-17, and OPG production in neutrophils from arthritic mice. Mediators Inflamm 2014:643406CrossRefGoogle Scholar
  15. 15.
    Kim JY, Park YJ, Kim KJ, Choi JJ, Kim WU, Cho CS (2013) Osteoprotegerin causes apoptosis of endothelial progenitor cells by induction of oxidative stress. Arthritis Rheum 65:2172–2182CrossRefGoogle Scholar
  16. 16.
    Lee J, Lee S, Lee CY, Seo HH, Shin S, Choi JW, Kim SW, Park JC, Lim S, Hwang KC (2017) Adipose-derived stem cell-released osteoprotegerin protects cardiomyocytes from reactive oxygen species-induced cell death. Stem Cell Res Ther 8:195CrossRefGoogle Scholar
  17. 17.
    Eelen G, de Zeeuw P, Simons M, Carmeliet P (2015) Endothelial cell metabolism in normal and diseased vasculature. Circ Res 116:1231–1244CrossRefGoogle Scholar
  18. 18.
    Rochette L, Lorin J, Zeller M, Guilland JC, Lorgis L, Cottin Y, Vergely C (2013) Nitric oxide synthase inhibition and oxidative stress in cardiovascular diseases: possible therapeutic targets? Pharmacol Ther 140:239–257CrossRefGoogle Scholar
  19. 19.
    Culic O, Gruwel ML, Schrader J (1997) Energy turnover of vascular endothelial cells. Am J Physiol 273:C205–C213CrossRefGoogle Scholar
  20. 20.
    Schoors S, Bruning U, Missiaen R, Queiroz KC, Borgers G, Elia I, Zecchin A, Cantelmo AR, Christen S, Goveia J, Heggermont W, Godde L, Vinckier S, Van Veldhoven PP, Eelen G, Schoonjans L, Gerhardt H, Dewerchin M, Baes M, De Bock K, Ghesquiere B, Lunt SY, Fendt SM, Carmeliet P (2015) Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520:192–197CrossRefGoogle Scholar
  21. 21.
    Iso T, Maeda K, Hanaoka H, Suga T, Goto K, Syamsunarno MR, Hishiki T, Nagahata Y, Matsui H, Arai M, Yamaguchi A, Abumrad NA, Sano M, Suematsu M, Endo K, Hotamisligil GS, Kurabayashi M (2013) Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle. Arterioscler Thromb Vasc Biol 33:2549–2557CrossRefGoogle Scholar
  22. 22.
    Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, van Meeteren LA, Samen E, Lu L, Vanwildemeersch M, Klar J, Genove G, Pietras K, Stone-Elander S, Claesson-Welsh L, Yla-Herttuala S, Lindahl P, Eriksson U (2010) Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464:917–921CrossRefGoogle Scholar
  23. 23.
    Ingwall JS (2009) Energy metabolism in heart failure and remodelling. Cardiovasc Res 81:412–419CrossRefGoogle Scholar
  24. 24.
    Ashrafian H, Frenneaux MP, Opie LH (2007) Metabolic mechanisms in heart failure. Circulation 116:434–448CrossRefGoogle Scholar
  25. 25.
    Kobayashi-Sakamoto M, Hirose K, Isogai E, Chiba I (2004) NF-kappaB-dependent induction of osteoprotegerin by Porphyromonas gingivalis in endothelial cells. Biochem Biophys Res Commun 315:107–112CrossRefGoogle Scholar
  26. 26.
    Kobayashi-Sakamoto M, Isogai E, Hirose K, Chiba I (2008) Role of alphav integrin in osteoprotegerin-induced endothelial cell migration and proliferation. Microvasc Res 76:139–144CrossRefGoogle Scholar
  27. 27.
    Lommi JI, Kovanen PT, Jauhiainen M, Lee-Rueckert M, Kupari M, Helske S (2011) High-density lipoproteins (HDL) are present in stenotic aortic valves and may interfere with the mechanisms of valvular calcification. Atherosclerosis 219:538–544CrossRefGoogle Scholar
  28. 28.
    Rochette L, Zeller M, Cottin Y, Vergely C (2014) Diabetes, oxidative stress and therapeutic strategies. Biochim Biophys Acta 1840:2709–2729CrossRefGoogle Scholar
  29. 29.
    Zhang J, Fu M, Myles D, Zhu X, Du J, Cao X, Chen YE (2002) PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS Lett 521:180–184CrossRefGoogle Scholar
  30. 30.
    Kleemann R, Bureeva S, Perlina A, Kaput J, Verschuren L, Wielinga PY, Hurt-Camejo E, Nikolsky Y, van Ommen B, Kooistra T (2011) A systems biology strategy for predicting similarities and differences of drug effects: evidence for drug-specific modulation of inflammation in atherosclerosis. BMC Syst Biol 5:125CrossRefGoogle Scholar
  31. 31.
    Stangl K, Stangl V (2010) The ubiquitin-proteasome pathway and endothelial (dys)function. Cardiovasc Res 85:281–290CrossRefGoogle Scholar
  32. 32.
    Laina A, Stellos K, Stamatelopoulos K (2017) Vascular ageing: Underlying mechanisms and clinical implications. Exp Gerontol 109:16–30CrossRefGoogle Scholar
  33. 33.
    Depre C, Wang Q, Yan L, Hedhli N, Peter P, Chen L, Hong C, Hittinger L, Ghaleh B, Sadoshima J, Vatner DE, Vatner SF, Madura K (2006) Activation of the cardiac proteasome during pressure overload promotes ventricular hypertrophy. Circulation 114:1821–1828CrossRefGoogle Scholar
  34. 34.
    Ueland T, Yndestad A, Oie E, Florholmen G, Halvorsen B, Froland SS, Simonsen S, Christensen G, Gullestad L, Aukrust P (2005) Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure. Circulation 111:2461–2468CrossRefGoogle Scholar
  35. 35.
    di Giuseppe R, Biemann R, Wirth J, Menzel J, Isermann B, Stangl GI, Fritsche A, Boeing H, Schulze MB, Weikert C (2017) Plasma osteoprotegerin, its correlates, and risk of heart failure: a prospective cohort study. Eur J Epidemiol 32:113–123CrossRefGoogle Scholar
  36. 36.
    Min JK, Kim YM, Kim YM, Kim EC, Gho YS, Kang IJ, Lee SY, Kong YY, Kwon YG (2003) Vascular endothelial growth factor up-regulates expression of receptor activator of NF-kappa B (RANK) in endothelial cells. Concomitant increase of angiogenic responses to RANK ligand. J Biol Chem 278:39548–39557CrossRefGoogle Scholar
  37. 37.
    Potente M, Carmeliet P (2017) The link between angiogenesis and endothelial metabolism. Annu Rev Physiol 79:43–66CrossRefGoogle Scholar
  38. 38.
    Kobayashi-Sakamoto M, Isogai E, Holen I (2010) Osteoprotegerin induces cytoskeletal reorganization and activates FAK, Src, and ERK signaling in endothelial cells. Eur J Haematol 85:26–35Google Scholar
  39. 39.
    Dougall WC (2012) Molecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis. Clin Cancer Res 18:326–335CrossRefGoogle Scholar
  40. 40.
    Hwang HJ, Jung SH, Lee HC, Han NK, Bae IH, Lee M, Han YH, Kang YS, Lee SJ, Park HJ, Ko YG, Lee JS (2016) Identification of novel therapeutic targets in the secretome of ionizing radiation induced senescent tumor cells. Oncol Rep 35:841–850CrossRefGoogle Scholar
  41. 41.
    Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL (2014) Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344:630–634CrossRefGoogle Scholar
  42. 42.
    Rochette L, Zeller M, Cottin Y, Vergely C (2015) Growth and differentiation factor 11 (GDF11): functions in the regulation of erythropoiesis and cardiac regeneration. Pharmacol Ther 156:26–33CrossRefGoogle Scholar
  43. 43.
    Liu W, Zhou L, Zhou C, Zhang S, Jing J, Xie L, Sun N, Duan X, Jing W, Liang X, Zhao H, Ye L, Chen Q, Yuan Q (2016) GDF11 decreases bone mass by stimulating osteoclastogenesis and inhibiting osteoblast differentiation. Nat Commun 7:12794CrossRefGoogle Scholar
  44. 44.
    Luo J, Yang Z, Ma Y, Yue Z, Lin H, Qu G, Huang J, Dai W, Li C, Zheng C, Xu L, Chen H, Wang J, Li D, Siwko S, Penninger JM, Ning G, Xiao J, Liu M (2016) LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat Med 22:539–546CrossRefGoogle Scholar
  45. 45.
    Weitzmann MN, Ofotokun I (2016) Physiological and pathophysiological bone turnover—role of the immune system. Nat Rev 12:518–532Google Scholar
  46. 46.
    Goltzman D, Mannstadt M, Marcocci C (2018) Physiology of the calcium-parathyroid hormone-vitamin D axis. Front Horm Res 50:1–13CrossRefGoogle Scholar
  47. 47.
    Akbari S, Rasouli-Ghahroudi AA (2018) Vitamin K and bone metabolism: a review of the latest evidence in preclinical studies. Biomed Res Int 2018:4629383CrossRefGoogle Scholar
  48. 48.
    Schwalfenberg GK (2017) Vitamins K1 and K2: the emerging group of vitamins required for human health. J Nutr Metab 2017:6254836CrossRefGoogle Scholar
  49. 49.
    Roumeliotis S, Dounousi E, Eleftheriadis T, Liakopoulos V (2019) Association of the inactive circulating matrix Gla protein with vitamin K intake, calcification, mortality, and cardiovascular disease: a review. Int J Mol Scie 20:628CrossRefGoogle Scholar
  50. 50.
    Lok ZSY, Lyle AN (2019) Osteopontin in Vascular Disease. Arterioscler Thromb Vasc Biol:ATVBAHA118311577Google Scholar
  51. 51.
    Back M, Aranyi T, Cancela ML, Carracedo M, Conceicao N, Leftheriotis G, Macrae V, Martin L, Nitschke Y, Pasch A, Quaglino D, Rutsch F, Shanahan C, Sorribas V, Szeri F, Valdivielso P, Vanakker O, Kempf H (2018) Endogenous calcification inhibitors in the prevention of vascular calcification: a consensus statement from the COST action EuroSoftCalcNet. Front Cardiovasc Med 5:196CrossRefGoogle Scholar
  52. 52.
    Yiu AJ, Callaghan D, Sultana R, Bandyopadhyay BC (2015) Vascular calcification and stone disease: a new look towards the mechanism. J Cardiovasc Dev Dis 2:141–164CrossRefGoogle Scholar
  53. 53.
    Davaine JM, Quillard T, Brion R, Laperine O, Guyomarch B, Merlini T, Chatelais M, Guilbaud F, Brennan MA, Charrier C, Heymann D, Goueffic Y, Heymann MF (2014) Osteoprotegerin, pericytes and bone-like vascular calcification are associated with carotid plaque stability. PLoS ONE 9:e107642CrossRefGoogle Scholar
  54. 54.
    Navarro R, Compte M, Alvarez-Vallina L, Sanz L (2016) Immune regulation by pericytes: modulating innate and adaptive immunity. Front Immunol 7:480CrossRefGoogle Scholar
  55. 55.
    Hung CF, Mittelsteadt KL, Brauer R, McKinney BL, Hallstrand TS, Parks WC, Chen P, Schnapp LM, Liles WC, Duffield JS, Altemeier WA (2017) Lung pericyte-like cells are functional interstitial immune sentinel cells. Am J Physiol 312:L556–L567Google Scholar
  56. 56.
    Wu M, Rementer C, Giachelli CM (2013) Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int 93:365–373CrossRefGoogle Scholar
  57. 57.
    Schneeweis LA, Willard D, Milla ME (2005) Functional dissection of osteoprotegerin and its interaction with receptor activator of NF-kappaB ligand. J Biol Chem 280:41155–41164CrossRefGoogle Scholar
  58. 58.
    Garcia-Sanchez C, Posadas-Romero C, Posadas-Sanchez R, Carreon-Torres E, Rodriguez-Perez JM, Juarez-Rojas JG, Martinez-Sanchez C, Fragoso JM, Gonzalez-Pacheco H, Vargas-Alarcon G, Perez-Mendez O (2015) Low concentrations of phospholipids and plasma HDL cholesterol subclasses in asymptomatic subjects with high coronary calcium scores. Atherosclerosis 238:250–255CrossRefGoogle Scholar
  59. 59.
    Wang JC, Bennett M (2012) Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res 111:245–259CrossRefGoogle Scholar
  60. 60.
    Tziakas DN, Chalikias G, Pavlaki M, Kareli D, Gogiraju R, Hubert A, Bohm E, Stamoulis P, Drosos I, Kikas P, Mikroulis D, Giatromanolaki A, Georgiadis GS, Konstantinou F, Argyriou C, Munzel T, Konstantinides SV, Schafer K (2019) Lysed erythrocyte membranes promote vascular calcification: possible role of erythrocyte-derived nitric oxide. Circulation 139:2032–2048CrossRefGoogle Scholar
  61. 61.
    Tesauro M, Mauriello A, Rovella V, Annicchiarico-Petruzzelli M, Cardillo C, Melino G, Di Daniele N (2017) Arterial ageing: from endothelial dysfunction to vascular calcification. J Intern Med 281:471–482CrossRefGoogle Scholar
  62. 62.
    Saliques S, Teyssier JR, Vergely C, Lorgis L, Lorin J, Donzel A, Sicard P, Berchoud J, Ragot S, Touzery C, Cottin Y, Rochette L, Zeller M (2011) Smoking and FOS expression from blood leukocyte transcripts in patients with coronary artery disease. Atherosclerosis 219:931–936CrossRefGoogle Scholar
  63. 63.
    Jilka RL, O’Brien CA (2016) The role of osteocytes in age-related bone loss. Curr Osteoporos Rep 14:16–25CrossRefGoogle Scholar
  64. 64.
    Andrews-Hanna JR, Snyder AZ, Vincent JL, Lustig C, Head D, Raichle ME, Buckner RL (2007) Disruption of large-scale brain systems in advanced aging. Neuron 56:924–935CrossRefGoogle Scholar
  65. 65.
    Weiskopf D, Weinberger B, Grubeck-Loebenstein B (2009) The aging of the immune system. Transpl Int 22:1041–1050CrossRefGoogle Scholar
  66. 66.
    Hanada R, Leibbrandt A, Hanada T, Kitaoka S, Furuyashiki T, Fujihara H, Trichereau J, Paolino M, Qadri F, Plehm R, Klaere S, Komnenovic V, Mimata H, Yoshimatsu H, Takahashi N, von Haeseler A, Bader M, Kilic SS, Ueta Y, Pifl C, Narumiya S, Penninger JM (2009) Central control of fever and female body temperature by RANKL/RANK. Nature 462:505–509CrossRefGoogle Scholar
  67. 67.
    Shimamura M, Nakagami H, Osako MK, Kurinami H, Koriyama H, Zhengda P, Tomioka H, Tenma A, Wakayama K, Morishita R (2014) OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice. Proc Natl Acad Sci USA 111:8191–8196CrossRefGoogle Scholar
  68. 68.
    Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192CrossRefGoogle Scholar
  69. 69.
    Yamada S, Giachelli CM (2017) Vascular calcification in CKD-MBD: roles for phosphate, FGF23, and Klotho. Bone 100:87–93CrossRefGoogle Scholar
  70. 70.
    Diab DL, Watts NB (2014) Denosumab in osteoporosis. Expert Opin Drug Saf 13:247–253CrossRefGoogle Scholar
  71. 71.
    Riggs MM, Cremers S (2019) Pharmacometrics and systems pharmacology for metabolic bone diseases. Br J Clin Pharmacol 85(6):1136–1146CrossRefGoogle Scholar
  72. 72.
    Pietrzyk B, Smertka M, Chudek J (2017) Sclerostin: intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders. Adv Clin Exp Med 26:1283–1291CrossRefGoogle Scholar
  73. 73.
    Alique M, Ramirez-Carracedo R, Bodega G, Carracedo J, Ramirez R (2018) Senescent microvesicles a novel advance in molecular mechanisms of atherosclerotic calcification. Int J Mol Sci 19(7):2003CrossRefGoogle Scholar
  74. 74.
    Shanahan CM (2013) Mechanisms of vascular calcification in CKD-evidence for premature ageing? Nat Rev Nephrol 9:661–670CrossRefGoogle Scholar
  75. 75.
    Kranenburg G, Bartstra JW, Weijmans M, de Jong PA, Mali WP, Verhaar HJ, Visseren FLJ, Spiering W (2016) Bisphosphonates for cardiovascular risk reduction: a systematic review and meta-analysis. Atherosclerosis 252:106–115CrossRefGoogle Scholar
  76. 76.
    Wu MY, Li CJ, Yiang GT, Cheng YL, Tsai AP, Hou YT, Ho YC, Hou MF, Chu PY (2018) Molecular regulation of bone metastasis pathogenesis. Cell Physiol Biochem 46:1423–1438CrossRefGoogle Scholar
  77. 77.
    Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M, Yan J, Hua Y, Tiede BJ, Lu X, Haffty BG, Pantel K, Massague J, Kang Y (2011) VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell 20:701–714CrossRefGoogle Scholar
  78. 78.
    Weitzmann MN (2017) Bone and the immune system. Toxicol Pathol 45:911–924CrossRefGoogle Scholar
  79. 79.
    Kondegowda NG, Fenutria R, Pollack IR, Orthofer M, Garcia-Ocana A, Penninger JM, Vasavada RC (2015) Osteoprotegerin and denosumab stimulate human beta cell proliferation through inhibition of the receptor activator of NF-kappaB ligand pathway. Cell Metab 22:77–85CrossRefGoogle Scholar
  80. 80.
    Shirakawa J, Togashi Y, Sakamoto E, Kaji M, Tajima K, Orime K, Inoue H, Kubota N, Kadowaki T, Terauchi Y (2013) Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic beta-cells. Diabetes 62:3448–3458CrossRefGoogle Scholar
  81. 81.
    Terauchi Y, Takamoto I, Kubota N, Matsui J, Suzuki R, Komeda K, Hara A, Toyoda Y, Miwa I, Aizawa S, Tsutsumi S, Tsubamoto Y, Hashimoto S, Eto K, Nakamura A, Noda M, Tobe K, Aburatani H, Nagai R, Kadowaki T (2007) Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance. J Clin Invest 117:246–257CrossRefGoogle Scholar
  82. 82.
    Panizo S, Cardus A, Encinas M, Parisi E, Valcheva P, Lopez-Ongil S, Coll B, Fernandez E, Valdivielso JM (2009) RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway. Circ Res 104:1041–1048CrossRefGoogle Scholar
  83. 83.
    de Groot AF, Appelman-Dijkstra NM, van der Burg SH, Kroep JR (2018) The anti-tumor effect of RANKL inhibition in malignant solid tumors—a systematic review. Cancer Treat Rev 62:18–28CrossRefGoogle Scholar
  84. 84.
    Murakami K, Kobayashi Y, Uehara S, Suzuki T, Koide M, Yamashita T, Nakamura M, Takahashi N, Kato H, Udagawa N, Nakamura Y (2017) A Jak1/2 inhibitor, baricitinib, inhibits osteoclastogenesis by suppressing RANKL expression in osteoblasts in vitro. PLoS ONE 12:e0181126CrossRefGoogle Scholar
  85. 85.
    Evans BA, Elford C, Pexa A, Francis K, Hughes AC, Deussen A, Ham J (2006) Human osteoblast precursors produce extracellular adenosine, which modulates their secretion of IL-6 and osteoprotegerin. J Bone Miner Res 21:228–236CrossRefGoogle Scholar
  86. 86.
    St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F, Carlson-Donohoe H, Lederman RJ, Chen MY, Yang D, Siegenthaler MP, Arduino C, Mancini C, Freudenthal B, Stanescu HC, Zdebik AA, Chaganti RK, Nussbaum RL, Kleta R, Gahl WA, Boehm M (2011) NT5E mutations and arterial calcifications. N Engl J Med 364:432–442CrossRefGoogle Scholar
  87. 87.
    Burnstock G (2017) Purinergic signalling: therapeutic developments. Front Pharmacol 8:661CrossRefGoogle Scholar
  88. 88.
    Patel JJ, Zhu D, Opdebeeck B, D’Haese P, Millan JL, Bourne LE, Wheeler-Jones CPD, Arnett TR, MacRae VE, Orriss IR (2018) Inhibition of arterial medial calcification and bone mineralization by extracellular nucleotides: the same functional effect mediated by different cellular mechanisms. J Cell Physiol 233:3230–3243CrossRefGoogle Scholar
  89. 89.
    Abdel-Magid AF (2017) Inhibitors of CD73 may provide a treatment for cancer and autoimmune diseases. ACS Med Chem Lett 8:781–782CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Luc Rochette
    • 1
    Email author
  • Alexandre Meloux
    • 1
  • Eve Rigal
    • 1
  • Marianne Zeller
    • 1
  • Gabriel Malka
    • 2
  • Yves Cottin
    • 1
    • 3
  • Catherine Vergely
    • 1
  1. 1.Equipe d’Accueil (EA 7460): Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne – Franche Comté, Faculté des Sciences de SantéDijonFrance
  2. 2.Institut de formation en Biotechnologie et Ingénierie Biomédicale (IFR2B)Université Mohammed VI PolytechniqueBen-GuerirMorocco
  3. 3.Service de Cardiologie-CHU-DijonDijonFrance

Personalised recommendations