Advertisement

Inflammatory Bowel Disease: Effects on Bone and Mechanisms

  • Francisco A. SylvesterEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1033)

Abstract

Inflammatory bowel disease (IBD) is associated with decreased bone mass and alterations in bone geometry from the time of diagnosis, before anti-inflammatory therapy is instituted. Deficits in bone mass can persist despite absence of symptoms of active IBD. The effects of IBD on the skeleton are complex. Protein-calorie malnutrition, inactivity, hypogonadism, deficits in calcium intake and vitamin D consumption and synthesis, stunted growth in children, decreased skeletal muscle mass, and inflammation all likely play a role. Preliminary studies suggest that the dysbiotic intestinal microbial flora present in IBD may also affect bone at a distance. Several mechanisms are possible. T cells activated by the gut microbiota may serve as “inflammatory shuttles” between the intestine and bone. Microbe-associated molecular patterns leaked into the circulation in IBD may activate immune responses in the bone marrow by immune cells and by osteocytes, osteoblasts, and osteoclasts that lead to decreased bone formation and increased resorption. Finally, intestinal microbial metabolites such as H2S may also affect bone cell function. Uncovering these mechanisms will enable the design of microbial cocktails to help restore bone mass in patients with IBD.

Keywords

Inflammatory bowel disease Crohn disease Ulcerative colitis Osteoporosis Cachexia Osteoblasts Osteoclasts Cytokines Osteoprotegerin Receptor activator of nuclear factor κΒ 

References

  1. 1.
    Sylvester FA, Gordon CM, Thayu M, Burnham JM, Denson LA, Essers J, et al. Report of the CCFA pediatric bone, growth and muscle health workshop, New York City, November 11–12, 2011, with updates. Inflamm Bowel Dis. 2013;19(13):2919–26.PubMedCrossRefGoogle Scholar
  2. 2.
    Targownik LE, Bernstein CN, Leslie WD. Risk factors and management of osteoporosis in inflammatory bowel disease. Curr Opin Gastroenterol. 2014;30:168–74.PubMedCrossRefGoogle Scholar
  3. 3.
    Bianchi ML, Leonard MB, Bechtold S, Hogler W, Mughal MZ, Schonau E, et al. Bone health in children and adolescents with chronic diseases that may affect the skeleton: the 2013 ISCD pediatric official positions. J Clin Densitom. 2014;17(2):281–94.PubMedCrossRefGoogle Scholar
  4. 4.
    Sylvester FA, Wyzga N, Hyams JS, Davis PM, Lerer T, Vance K, et al. Natural history of bone metabolism and bone mineral density in children with inflammatory bowel disease. Inflamm Bowel Dis. 2007;13(1):42–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Dubner SE, Shults J, Baldassano RN, Zemel BS, Thayu M, Burnham JM, et al. Longitudinal assessment of bone density and structure in an incident cohort of children with Crohn’s disease. Gastroenterology. 2009;136(1):123–30.PubMedCrossRefGoogle Scholar
  6. 6.
    Werkstetter KJ, Pozza SB, Filipiak-Pittroff B, Schatz SB, Prell C, Bufler P, et al. Long-term development of bone geometry and muscle in pediatric inflammatory bowel disease. Am J Gastroenterol. 2011;106:988–98.PubMedCrossRefGoogle Scholar
  7. 7.
    Thayu M, Shults J, Burnham JM, Zemel BS, Baldassano RN, Leonard MB. Gender differences in body composition deficits at diagnosis in children and adolescents with Crohn’s disease. Inflamm Bowel Dis. 2007;13(9):1121–8.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Sylvester FA, Leopold S, Lincoln M, Hyams JS, Griffiths AM, Lerer T. A two-year longitudinal study of persistent lean tissue deficits in children with Crohn’s disease. Clin Gastroenterol Hepatol. 2009;7(4):452–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Leonard MB. Glucocorticoid-induced osteoporosis in children: impact of the underlying disease. Pediatrics. 2007;119(Suppl 2):S166–74.PubMedCrossRefGoogle Scholar
  10. 10.
    Tsampalieros A, Lam CK, Spencer JC, Thayu M, Shults J, Zemel BS, et al. Long-term inflammation and glucocorticoid therapy impair skeletal modeling during growth in childhood Crohn disease. J Clin Endocrinol Metab. 2013;98(8):3438–45.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Bechtold S, Alberer M, Arenz T, Putzker S, Filipiak-Pittroff B, Schwarz HP, et al. Reduced muscle mass and bone size in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2010;16(2):216–25.PubMedCrossRefGoogle Scholar
  12. 12.
    Ward LM, Rauch F, Matzinger MA, Benchimol EI, Boland M, Mack DR. Iliac bone histomorphometry in children with newly diagnosed inflammatory bowel disease. Osteoporos Int. 2010;21:331–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Sylvester FA, Davis PM, Wyzga N, Hyams JS, Lerer T. Are activated T cells regulators of bone metabolism in children with Crohn disease? J Pediatr. 2006;148(4):461–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Evans WJ. Skeletal muscle loss: cachexia, sarcopenia, and inactivity. Am J Clin Nutr. 2010;91(4):1123S–7S.PubMedCrossRefGoogle Scholar
  15. 15.
    Rauch F, Bailey DA, Baxter-Jones A, Mirwald R, Faulkner R. The ‘muscle-bone unit’ during the pubertal growth spurt. Bone. 2004;34(5):771–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Bechtold S, Alberer M, Arenz T, Putzker S, Filipiak-Pittroff B, Schwarz HP, et al. Reduced muscle mass and bone size in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2009;16:216–25.CrossRefGoogle Scholar
  17. 17.
    Bernstein CN, Blanchard JF, Leslie W, Wajda A, Yu BN. The incidence of fracture among patients with inflammatory bowel disease. A population-based cohort study. Ann Intern Med. 2000;133(10):795–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Loftus EJ, Crowson CS, Sandborn WJ, Tremaine WJ, O’Fallon WM, Melton LJ 3rd. Long-term fracture risk in patients with Crohn’s disease: a population-based study in Olmsted County, Minnesota. Gastroenterology. 2002;123(2):468–75.Google Scholar
  19. 19.
    Siffledeen JS, Siminoski K, Jen H, Fedorak RN. Vertebral fractures and role of low bone mineral density in Crohn’s disease. Clin Gastroenterol Hepatol. 2007;5(6):721–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Semeao EJ, Stallings VA, Peck SN, Piccoli DA. Vertebral compression fractures in pediatric patients with Crohn’s disease. Gastroenterology. 1997;112(5):1710–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Persad R, Jaffer I, Issenman RM. The prevalence of long bone fractures in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2006;43(5):597–602.PubMedCrossRefGoogle Scholar
  22. 22.
    Kappelman MD, Galanko JA, Porter CQ, Sandler RS. Risk of diagnosed fractures in children with inflammatory bowel diseases. Inflamm Bowel Dis. 2011;17:1125–30.PubMedCrossRefGoogle Scholar
  23. 23.
    Dresner-Pollak R, Gelb N, Rachmilewitz D, Karmeli F, Weinreb M. Interleukin 10-deficient mice develop osteopenia, decreased bone formation, and mechanical fragility of long bones. Gastroenterology. 2004;127(3):792–801.PubMedCrossRefGoogle Scholar
  24. 24.
    Ciucci T, Ibanez L, Boucoiran A, Birgy-Barelli E, Pene J, Abou-Ezzi G, et al. Bone marrow Th17 TNFalpha cells induce osteoclast differentiation, and link bone destruction to IBD. Gut. 2015;64(7):1072–81.PubMedCrossRefGoogle Scholar
  25. 25.
    Ashcroft AJ, Cruickshank SM, Croucher PI, Perry MJ, Rollinson S, Lippitt JM, et al. Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity. 2003;19(6):849–61.PubMedCrossRefGoogle Scholar
  26. 26.
    Byrne FR, Morony S, Warmington K, Geng Z, Brown HL, Flores SA, et al. CD4+CD45RBHi T cell transfer induced colitis in mice is accompanied by osteopenia which is treatable with recombinant human osteoprotegerin. Gut. 2005;54(1):78–86.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Gilbert L, He X, Farmer P, Boden S, Kozlowski M, Rubin J, et al. Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology. 2000;141(11):3956–64.PubMedCrossRefGoogle Scholar
  28. 28.
    Lin CL, Moniz C, Chambers TJ, Chow JW. Colitis causes bone loss in rats through suppression of bone formation. Gastroenterology. 1996;111(5):1263–71.PubMedCrossRefGoogle Scholar
  29. 29.
    Hamdani G, Gabet Y, Rachmilewitz D, Karmeli F, Bab I, Dresner-Pollak R. Dextran sodium sulfate-induced colitis causes rapid bone loss in mice. Bone. 2008;43(5):945–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Harris L, Senagore P, Young VB, McCabe LR. Inflammatory bowel disease causes reversible suppression of osteoblast and chondrocyte function in mice. Am J Physiol Gastrointest Liver Physiol. 2009;296(5):G1020–9.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Irwin R, Lee T, Young VB, Parameswaran N, McCabe LR. Colitis-induced bone loss is gender dependent and associated with increased inflammation. Inflamm Bowel Dis. 2013;19:1586–97.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Azcue M, Rashid M, Griffiths A, Pencharz PB. Energy expenditure and body composition in children with Crohn’s disease: effect of enteral nutrition and treatment with prednisolone. Gut. 1997;41(2):203–8.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Owczarek D, Rodacki T, Domagala-Rodacka R, Cibor D, Mach T. Diet and nutritional factors in inflammatory bowel diseases. World J Gastroenterol. 2016;22(3):895–905.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Kabbani TA, Koutroubakis IE, Schoen RE, Ramos-Rivers C, Shah N, Swoger J, et al. Association of vitamin D level with clinical status in inflammatory bowel disease: a 5-year longitudinal study. Am J Gastroenterol. 2016;111:712–9.Google Scholar
  35. 35.
    Nakajima S, Iijima H, Egawa S, Shinzaki S, Kondo J, Inoue T, et al. Association of vitamin K deficiency with bone metabolism and clinical disease activity in inflammatory bowel disease. Nutrition. 2011;27(10):1023–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Simek RZ, Prince J, Syed S, Sauer CG, Martineau B, Hofmekler T, et al. Pilot study evaluating efficacy of two regimens for hypovitaminosis D repletion in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2016;62:252–8.Google Scholar
  37. 37.
    Schulze KJ, O’Brien KO, Germain-Lee EL, Booth SL, Leonard A, Rosenstein BJ. Calcium kinetics are altered in clinically stable girls with cystic fibrosis. J Clin Endocrinol Metab. 2004;89(7):3385–91.PubMedCrossRefGoogle Scholar
  38. 38.
    Thayu M, Denson LA, Shults J, Zemel BS, Burnham JM, Baldassano RN, et al. Determinants of changes in linear growth and body composition in incident pediatric Crohn’s disease. Gastroenterology. 2010;139:430–8.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Difedele LM, He J, Bonkowski EL, Han X, Held MA, Bohan A, et al. Tumor necrosis factor-a blockade restores growth hormone signaling in murine colitis. Gastroenterology. 2005;128(5):1278–91.PubMedCrossRefGoogle Scholar
  40. 40.
    Reich KM, Fedorak RN, Madsen K, Kroeker KI. Vitamin D improves inflammatory bowel disease outcomes: basic science and clinical review. World J Gastroenterol WJG. 2014;20(17):4934–47.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhu Y, Mahon BD, Froicu M, Cantorna MT. Calcium and 1 alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. Eur J Immunol. 2005;35(1):217–24.PubMedCrossRefGoogle Scholar
  42. 42.
    Froicu M, Weaver V, Wynn TA, McDowell MA, Welsh JE, Cantorna MT. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol Endocrinol. 2003;17(12):2386–92.PubMedCrossRefGoogle Scholar
  43. 43.
    Cantorna MT, Munsick C, Bemiss C, Mahon BD. 1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. J Nutr. 2000;130(11):2648–52.PubMedGoogle Scholar
  44. 44.
    Wang F, Johnson RL, DeSmet ML, Snyder PW, Fairfax KC, Fleet JC. Vitamin D receptor-dependent signaling protects mice from dextran sulfate sodium-induced colitis. Endocrinology. 2017;Google Scholar
  45. 45.
    Liu W, Chen Y, Golan MA, Annunziata ML, Du J, Dougherty U, et al. Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis. J Clin Invest. 2013;123:3983–96.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Hyams JS, Wyzga N, Kreutzer DL, Justinich CJ, Gronowicz GA. Alterations in bone metabolism in children with inflammatory bowel disease: an in vitro study. J Pediatr Gastroenterol Nutr. 1997;24(3):289–95.PubMedCrossRefGoogle Scholar
  47. 47.
    Varghese S, Wyzga N, Griffiths AM, Sylvester FA. Effects of serum from children with newly diagnosed Crohn disease on primary cultures of rat osteoblasts. J Pediatr Gastroenterol Nutr. 2002;35(5):641–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Sylvester FA, Wyzga N, Hyams JS, Gronowicz GA. Effect of Crohn’s disease on bone metabolism in vitro: a role for interleukin-6. J Bone Miner Res. 2002;17(4):695–702.PubMedCrossRefGoogle Scholar
  49. 49.
    Kaneki H, Guo R, Chen D, Yao Z, Schwarz EM, Zhang YE, et al. Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem. 2006;281(7):4326–33.PubMedCrossRefGoogle Scholar
  50. 50.
    Gilbert LC, Chen H, Lu X, Nanes MS. Chronic low dose tumor necrosis factor-alpha (TNF) suppresses early bone accrual in young mice by inhibiting osteoblasts without affecting osteoclasts. Bone. 2013;56(1):174–83.PubMedCrossRefGoogle Scholar
  51. 51.
    Yamazaki M, Fukushima H, Shin M, Katagiri T, Doi T, Takahashi T, et al. Tumor necrosis factor alpha represses bone morphogenetic protein (BMP) signaling by interfering with the DNA binding of Smads through the activation of NF-kappaB. J Biol Chem. 2009;284(51):35987–95.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Lee HL, Yi T, Woo KM, Ryoo HM, Kim GS, Baek JH. Msx2 mediates the inhibitory action of TNF-alpha on osteoblast differentiation. Exp Mol Med. 2010;42(6):437–45.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Jang WG, Jeong BC, Kim EJ, Choi H, Oh SH, Kim DK, et al. Cyclic AMP response element-binding protein H (CREBH) mediates the inhibitory actions of tumor necrosis factor alpha in osteoblast differentiation by stimulating Smad1 degradation. J Biol Chem. 2015;290(21):13556–66.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Shen F, Ruddy MJ, Plamondon P, Gaffen SL. Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-a-induced genes in bone cells. J Leukoc Biol. 2005;77(3):388–99.PubMedCrossRefGoogle Scholar
  55. 55.
    Uno JK, Kolek OI, Hines ER, Xu H, Timmermann BN, Kiela PR, et al. The role of tumor necrosis factor-a in down-regulation of osteoblast Phex gene expression in experimental murine colitis. Gastroenterology. 2006;131(2):497–509.PubMedCrossRefGoogle Scholar
  56. 56.
    Majewski PM, Thurston RD, Ramalingam R, Kiela PR, Ghishan FK. Cooperative role of NF-{kappa}B and poly(ADP-ribose) polymerase 1 (PARP-1) in the TNF-induced inhibition of PHEX expression in osteoblasts. J Biol Chem. 2010;285(45):34828–38.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Thayu M, Leonard MB, Hyams JS, Crandall WV, Kugathasan S, Otley AR, et al. Improvement in biomarkers of bone formation during infliximab therapy in pediatric Crohn’s disease: results of the REACH study. Clin Gastroenterol Hepatol. 2008;6(12):1378–84.PubMedCrossRefGoogle Scholar
  58. 58.
    Griffin LM, Thayu M, Baldassano RN, DeBoer MD, Zemel BS, Denburg MR, et al. Improvements in bone density and structure during anti-TNF-alpha therapy in pediatric Crohn’s disease. J Clin Endocrinol Metab. 2015;100(7):2630–9.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000;408(6812):600–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Sasaki H, Hou L, Belani A, Wang CY, Uchiyama T, Muller R, et al. IL-10, but not IL-4, suppresses infection-stimulated bone resorption in vivo. J Immunol. 2000;165(7):3626–30.PubMedCrossRefGoogle Scholar
  61. 61.
    Park-Min KH, Ji JD, Antoniv T, Reid AC, Silver RB, Humphrey MB, et al. IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression. J Immunol. 2009;183(4):2444–55.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Yoshimatsu M, Kitaura H, Fujimura Y, Eguchi T, Kohara H, Morita Y, et al. IL-12 inhibits TNF-alpha induced osteoclastogenesis via a T cell-independent mechanism in vivo. Bone. 2009;45(5):1010–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Kitaura H, Fujimura Y, Yoshimatsu M, Kohara H, Morita Y, Aonuma T, et al. IL-12- and IL-18-mediated, nitric oxide-induced apoptosis in TNF-alpha-mediated osteoclastogenesis of bone marrow cells. Calcif Tissue Int. 2011;89(1):65–73.PubMedCrossRefGoogle Scholar
  64. 64.
    Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Tyagi AM, Mansoori MN, Srivastava K, Khan MP, Kureel J, Dixit M, et al. Enhanced immunoprotective effects by anti-IL-17 antibody translates to improved skeletal parameters under estrogen deficiency compared with anti-RANKL and anti-TNF-alpha antibodies. J Bone Miner Res. 2014;29(9):1981–92.PubMedCrossRefGoogle Scholar
  66. 66.
    Van Bezooijen RL, Farih-Sips HC, Papapoulos SE, Lowik CW. Interleukin-17: a new bone acting cytokine in vitro. J Bone Miner Res. 1999;14(9):1513–21.CrossRefGoogle Scholar
  67. 67.
    Yago T, Nanke Y, Ichikawa N, Kobashigawa T, Mogi M, Kamatani N, et al. IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-alpha antibody: a novel mechanism of osteoclastogenesis by IL-17. J Cell Biochem. 2009;108(4):947–55.PubMedCrossRefGoogle Scholar
  68. 68.
    Balani D, Aeberli D, Hofstetter W, Seitz M. Interleukin-17A stimulates granulocyte-macrophage colony-stimulating factor release by murine osteoblasts in the presence of 1,25-dihydroxyvitamin D(3) and inhibits murine osteoclast development in vitro. Arthritis Rheum. 2013;65(2):436–46.PubMedCrossRefGoogle Scholar
  69. 69.
    Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103(9):1345–52.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309–19.PubMedCrossRefGoogle Scholar
  71. 71.
    Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997;390(6656):175–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397(6717):315–23.PubMedCrossRefGoogle Scholar
  73. 73.
    Summers deLuca L, Gommerman JL. Fine-tuning of dendritic cell biology by the TNF superfamily. Nat Rev Immunol. 2012;12(5):339–51.PubMedGoogle Scholar
  74. 74.
    Yun TJ, Chaudhary PM, Shu GL, Frazer JK, Ewings MK, Schwartz SM, et al. OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40. J Immunol. 1998;161(11):6113–21.PubMedGoogle Scholar
  75. 75.
    Chino T, Draves KE, Clark EA. Regulation of dendritic cell survival and cytokine production by osteoprotegerin. J Leukoc Biol. 2009;86(4):933–40.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Nahidi L, Leach ST, Sidler MA, Levin A, Lemberg DA, Day AS. Osteoprotegerin in pediatric Crohn’s disease and the effects of exclusive enteral nutrition. Inflamm Bowel Dis. 2011;17(2):516–23.PubMedCrossRefGoogle Scholar
  77. 77.
    Maruyama K, Takada Y, Ray N, Kishimoto Y, Penninger JM, Yasuda H, et al. Receptor activator of NF-kappa B ligand and osteoprotegerin regulate proinflammatory cytokine production in mice. J Immunol. 2006;177(6):3799–805.PubMedCrossRefGoogle Scholar
  78. 78.
    Franchimont N, Reenaers C, Lambert C, Belaiche J, Bours V, Malaise M, et al. Increased expression of receptor activator of NF-kappaB ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin in the colon of Crohn’s disease patients. Clin Exp Immunol. 2004;138(3):491–8.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Arijs I, Li K, Toedter G, Quintens R, Van Lommel L, Van Steen K, et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut. 2009;58:1612–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Sylvester FA, Turner D, Draghi A 2nd, Uuosoe K, McLernon R, Koproske K, et al. Fecal osteoprotegerin may guide the introduction of second-line therapy in hospitalized children with ulcerative colitis. Inflamm Bowel Dis. 2011;17(8):1726–30.PubMedCrossRefGoogle Scholar
  81. 81.
    Nemoto Y, Kanai T, Makita S, Okamoto R, Totsuka T, Takeda K, et al. Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis. Gastroenterology. 2007;132(1):176–89.PubMedCrossRefGoogle Scholar
  82. 82.
    Nemoto Y, Kanai T, Takahara M, Oshima S, Nakamura T, Okamoto R, et al. Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells. Gut. 2013;62(8):1142–52.PubMedCrossRefGoogle Scholar
  83. 83.
    Takayanagi H. Osteoimmunology in 2014: two-faced immunology-from osteogenesis to bone resorption. Nat Rev Rheumatol. 2015;11(2):74–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999;402(6759):304–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol. 1998;160(7):3513–21.PubMedGoogle Scholar
  86. 86.
    Adamopoulos IE, Chao CC, Geissler R, Laface D, Blumenschein W, Iwakura Y, et al. Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors. Arthritis Res Ther. 2010;12(1):R29.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Li JY, D’Amelio P, Robinson J, Walker LD, Vaccaro C, Luo T, et al. IL-17A is increased in humans with primary hyperparathyroidism and mediates PTH-induced bone loss in mice. Cell Metab. 2015;22(5):799–810.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A. 2015;112(22):7061–6.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Zou L, Barnett B, Safah H, Larussa VF, Evdemon-Hogan M, Mottram P, et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res. 2004;64(22):8451–5.PubMedCrossRefGoogle Scholar
  90. 90.
    Tokoyoda K, Zehentmeier S, Hegazy AN, Albrecht I, Grun JR, Lohning M, et al. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity. 2009;30(5):721–30.PubMedCrossRefGoogle Scholar
  91. 91.
    Kelchtermans H, Geboes L, Mitera T, Huskens D, Leclercq G, Matthys P. Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis. Ann Rheum Dis. 2009;68(5):744–50.PubMedCrossRefGoogle Scholar
  92. 92.
    Terauchi M, Li JY, Bedi B, Baek KH, Tawfeek H, Galley S, et al. T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab. 2009;10(3):229–40.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Yang S, Takahashi N, Yamashita T, Sato N, Takahashi M, Mogi M, et al. Muramyl dipeptide enhances osteoclast formation induced by lipopolysaccharide, IL-1a, and TNF-a through nucleotide-binding oligomerization domain 2-mediated signaling in osteoblasts. J Immunol. 2005;175(3):1956–64.PubMedCrossRefGoogle Scholar
  94. 94.
    Chang MK, Raggatt LJ, Alexander KA, Kuliwaba JS, Fazzalari NL, Schroder K, et al. Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J Immunol. 2008;181(2):1232–44.PubMedCrossRefGoogle Scholar
  95. 95.
    Guihard P, Danger Y, Brounais B, David E, Brion R, Delecrin J, et al. Induction of osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling. Stem Cells. 2012;30(4):762–72.PubMedCrossRefGoogle Scholar
  96. 96.
    Laurent MR, Dubois V, Claessens F, Verschueren SM, Vanderschueren D, Gielen E, et al. Muscle-bone interactions: from experimental models to the clinic? A critical update. Mol Cell Endocrinol. 2015;Google Scholar
  97. 97.
    Werkstetter KJ, Ullrich J, Schatz SB, Prell C, Koletzko B, Koletzko S. Lean body mass, physical activity and quality of life in paediatric patients with inflammatory bowel disease and in healthy controls. J Crohns Colitis. 2012;Google Scholar
  98. 98.
    DeBoer MD, Denson LA. Delays in puberty, growth, and accrual of bone mineral density in pediatric Crohn’s disease: despite temporal changes in disease severity, the need for monitoring remains. J Pediatr. 2013;163(1):17–22.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Zhao G, Monier-Faugere MC, Langub MC, Geng Z, Nakayama T, Pike JW, et al. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology. 2000;141(7):2674–82.PubMedCrossRefGoogle Scholar
  100. 100.
    Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, Ahmad T, et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2015;387:156–67.PubMedCrossRefGoogle Scholar
  102. 102.
    Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Bock J, Martinez-Naves E, et al. Paneth cells as a site of origin for intestinal inflammation. Nature. 2013;503(7475):272–6.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Wu Y, Yang M, Fan J, Peng Y, Deng L, Ding Y, et al. Deficiency of osteoblastic Arl6ip5 impaired osteoblast differentiation and enhanced osteoclastogenesis via disturbance of ER calcium homeostasis and induction of ER stress-mediated apoptosis. Cell Death Dis. 2014;5:e1464.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Murakami T, Saito A, Hino S, Kondo S, Kanemoto S, Chihara K, et al. Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation. Nat Cell Biol. 2009;11(10):1205–11.PubMedCrossRefGoogle Scholar
  105. 105.
    Saito A, Ochiai K, Kondo S, Tsumagari K, Murakami T, Cavener DR, et al. Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem. 2011;286(6):4809–18.PubMedCrossRefGoogle Scholar
  106. 106.
    Tohmonda T, Miyauchi Y, Ghosh R, Yoda M, Uchikawa S, Takito J, et al. The IRE1alpha-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix. EMBO Rep. 2011;12(5):451–7.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Tohmonda T, Yoda M, Mizuochi H, Morioka H, Matsumoto M, Urano F, et al. The IRE1alpha-XBP1 pathway positively regulates parathyroid hormone (PTH)/PTH-related peptide receptor expression and is involved in pth-induced osteoclastogenesis. J Biol Chem. 2013;288(3):1691–5.PubMedCrossRefGoogle Scholar
  108. 108.
    Tohmonda T, Yoda M, Iwawaki T, Matsumoto M, Nakamura M, Mikoshiba K, et al. IRE1alpha/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis. J Clin Invest. 2015;125(8):3269–79.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Cao SS, Luo KL, Shi L. Endoplasmic reticulum stress interacts with inflammation in human diseases. J Cell Physiol. 2016;231(2):288–94.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Baxt LA, Xavier RJ. Role of autophagy in the maintenance of intestinal homeostasis. Gastroenterology. 2015;Google Scholar
  111. 111.
    Kneissel M, Luong-Nguyen NH, Baptist M, Cortesi R, Zumstein-Mecker S, Kossida S, et al. Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts. Bone. 2004;35(5):1144–56.PubMedCrossRefGoogle Scholar
  112. 112.
    Zhao Y, Chen G, Zhang W, Xu N, Zhu JY, Jia J, et al. Autophagy regulates hypoxia-induced osteoclastogenesis through the HIF-1alpha/BNIP3 signaling pathway. J Cell Physiol. 2012;227(2):639–48.PubMedCrossRefGoogle Scholar
  113. 113.
    Sambandam Y, Townsend MT, Pierce JJ, Lipman CM, Haque A, Bateman TA, et al. Microgravity control of autophagy modulates osteoclastogenesis. Bone. 2014;61:125–31.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Liu F, Fang F, Yuan H, Yang D, Chen Y, Williams L, et al. Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation. J Bone Miner Res. 2013;28(11):2414–30.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Pantovic A, Krstic A, Janjetovic K, Kocic J, Harhaji-Trajkovic L, Bugarski D, et al. Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells. Bone. 2013;52(1):524–31.PubMedCrossRefGoogle Scholar
  116. 116.
    Nollet M, Santucci-Darmanin S, Breuil V, Al-Sahlanee R, Cros C, Topi M, et al. Autophagy in osteoblasts is involved in mineralization and bone homeostasis. Autophagy. 2014;10(11):1965–77.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Zhang L, Guo YF, Liu YZ, Liu YJ, Xiong DH, Liu XG, et al. Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD. J Bone Miner Res. 2010;25(7):1572–80.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Hernandez CJ, Guss JD, Luna M, Goldring SR. Links between the microbiome and bone. J Bone Miner Res. 2016;Google Scholar
  119. 119.
    Gevers D, Kugathasan S, Denson LA, Vazquez-Baeza Y, Van Treuren W, Ren B, et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe. 2014;15(3):382–92.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Knights D, Silverberg MS, Weersma RK, Gevers D, Dijkstra G, Huang H, et al. Complex host genetics influence the microbiome in inflammatory bowel disease. Genome Med. 2014;6(12):107.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Ohlsson C, Nigro G, Boneca IG, Backhed F, Sansonetti P, Sjogren K. Regulation of bone mass by the gut microbiota is dependent on NOD1 and NOD2 signaling. Cell Immunol. 2017;317:55–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Division Chief of Pediatric GastroenterologyThe University of North Carolina at Chapel HilChapel HillUSA

Personalised recommendations