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Osteocardiology: The Atherosclerotic Bone Paradox

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Osteocardiology

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Abstract

The bone paradox in the heart and the skeleton is a complex and elusive disease process. The signaling mechanisms have been determined individually, however, the final common pathway, which merges the processes have yet to be defined. This chapter will discuss the role of Wnt Signaling in the bone and in the heart to further expand on the concept of atherosclerosis in the heart and in the bone, and the role of lipid lowering may play in the long terms treatment of osteoporosis in addition to atherosclerosis.

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References

  1. Komori T, Yagi H, Nomura S, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755–64.

    Article  CAS  PubMed  Google Scholar 

  2. Nakashima K, Zhou X, Kunkel G, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108:17–29.

    Article  CAS  PubMed  Google Scholar 

  3. Subramaniam M, Harris SA, Oursler MJ, Rasmussen K, Riggs BL, Spelsberg TC. Identification of a novel TGF-beta-regulated gene encoding a putative zinc finger protein in human osteoblasts. Nucleic Acids Res. 1995;23:4907–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hefferan TE, Reinholz GG, Rickard DJ, et al. Overexpression of a nuclear protein, TIEG, mimics transforming growth factor-beta action in human osteoblast cells. J Biol Chem. 2000;275:20255–9.

    Article  CAS  PubMed  Google Scholar 

  5. Tachibana I, Imoto M, Adjei PN, et al. Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells. J Clin Invest. 1997;99:2365–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Johnsen SA, Subramaniam M, Janknecht R, Spelsberg TC. TGFbeta inducible early gene enhances TGFbeta/Smad-dependent transcriptional responses. Oncogene. 2002;21:5783–90.

    Article  CAS  PubMed  Google Scholar 

  7. Hefferan TE, Subramaniam M, Khosla S, Riggs BL, Spelsberg TC. Cytokine-specific induction of the TGF-beta inducible early gene (TIEG): regulation by specific members of the TGF-beta family. J Cell Biochem. 2000;78:380–90.

    Article  CAS  PubMed  Google Scholar 

  8. Bensamoun SF, Tsubone T, Subramaniam M, et al. Age-dependent changes in the mechanical properties of tail tendons in TGF-beta inducible early gene-1 knockout mice. J Appl Physiol. 2006;101:1419–24.

    Article  CAS  PubMed  Google Scholar 

  9. Johnsen SA, Subramaniam M, Katagiri T, Janknecht R, Spelsberg TC. Transcriptional regulation of Smad2 is required for enhancement of TGFbeta/Smad signaling by TGFbeta inducible early gene. J Cell Biochem. 2002;87:233–41.

    Article  CAS  PubMed  Google Scholar 

  10. Johnsen SA, Subramaniam M, Monroe DG, Janknecht R, Spelsberg TC. Modulation of transforming growth factor beta (TGFbeta)/Smad transcriptional responses through targeted degradation of TGFbeta-inducible early gene-1 by human seven in absentia homologue. J Biol Chem. 2002;277:30754–9.

    Article  CAS  PubMed  Google Scholar 

  11. Tsubone T, Moran SL, Subramaniam M, Amadio PC, Spelsberg TC, An KN. Effect of TGF-beta inducible early gene deficiency on flexor tendon healing. J Orthop Res. 2006;24:569–75.

    Article  CAS  PubMed  Google Scholar 

  12. Hawse J, Iwaniec UT, Bensamoun SF, Monroe DG, Peters KD, Ilharreborde B, Rajamannan NM, Oursler MJ, Turner RT, Spelsberg TC, Subramaniam M. TIEG-Null mice display an osteopenic gender-specific phenotype. Bone. 2008;42:1025–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hawse JR, Subramaniam M, Monroe DG, et al. Estrogen receptor beta isoform-specific induction of transforming growth factor beta-inducible early gene-1 in human osteoblast cells: an essential role for the activation function 1 domain. Mol Endocrinol (Baltimore, Md). 2008;22:1579–95.

    Article  CAS  Google Scholar 

  14. Taguchi M, Moran SL, Zobitz ME, et al. Wound-healing properties of transforming growth factor beta (TGF-beta) inducible early gene 1 (TIEG1) knockout mice. J Musculoskelet Res. 2008;11:63–9.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Venuprasad K, Huang H, Harada Y, et al. The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat Immunol. 2008;9:245–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Subramaniam M, Gorny G, Johnsen SA, et al. TIEG1 null mouse-derived osteoblasts are defective in mineralization and in support of osteoclast differentiation in vitro. Mol Cell Biol. 2005;25:1191–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Subramaniam M, Hawse JR, Bruinsma ES, et al. TGFbeta inducible early gene-1 directly binds to, and represses, the OPG promoter in osteoblasts. Biochem Biophys Res Commun. 2010;392:72–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Subramaniam M, Hawse JR, Rajamannan NM, Ingle JN, Spelsberg TC. Functional role of KLF10 in multiple disease processes. BioFactors (Oxford, England). 2010;36:8–18.

    CAS  Google Scholar 

  19. Cicek M, Vrabel A, Sturchio C, et al. TGF-beta inducible early gene 1 regulates osteoclast differentiation and survival by mediating the NFATc1, AKT, and MEK/ERK signaling pathways. PLoS One. 2011;6:e17522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bensamoun SF, Hawse JR, Subramaniam M, et al. TGFbeta inducible early gene-1 knockout mice display defects in bone strength and microarchitecture. Bone. 2006;39:1244–51.

    Article  CAS  PubMed  Google Scholar 

  21. Subramaniam M, Hawse JR, Johnsen SA, Spelsberg TC. Role of TIEG1 in biological processes and disease states. J Cell Biochem. 2007;102:539–48.

    Article  CAS  PubMed  Google Scholar 

  22. Yerges LM, Klei L, Cauley JA, et al. Candidate gene analysis of femoral neck trabecular and cortical volumetric bone mineral density in older men. J Bone Miner Res. 2010;25:330–8.

    Article  CAS  PubMed  Google Scholar 

  23. Hopwood B, Tsykin A, Findlay DM, Fazzalari NL. Gene expression profile of the bone microenvironment in human fragility fracture bone. Bone. 2009;44:87–101.

    Article  CAS  PubMed  Google Scholar 

  24. Subramaniam M, Cicek M, Pitel KS, et al. TIEG1 modulates beta-catenin sub-cellular localization and enhances Wnt signaling in bone. Nucleic Acids Res. 2017;45:5170–82.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Rajamannan NM. Atorvastatin attenuates bone loss and aortic valve atheroma in LDLR mice. Cardiology. 2015;132:11–5.

    Article  CAS  PubMed  Google Scholar 

  26. Rajamannan NM. The role of TIEG1 in calcific aortic valve disease. Journal of Bone and Mineral Metabolism. 2017;29(9):S136.

    Google Scholar 

  27. Rajamannan NM. Evans FJ, Aikawa E, et al. Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: Calcific aortic valve disease-2011 update. Circulation. 2011;124:1783–91.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Rajamannan NM, Subramaniam M, Rickard D, et al. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation. 2003;107:2181–4.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Caira FC, Stock SR, Gleason TG, et al. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. J Am Coll Cardiol. 2006;47:1707–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation. 2005;112:I229–34.

    PubMed  PubMed Central  Google Scholar 

  31. Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005;115:1210–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rajamannan NM. The role of Lrp5/6 in cardiac valve disease: experimental hypercholesterolemia in the ApoE−/− /Lrp5−/− mice. J Cell Biochem. 2011;112:2987–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rajamannan NM. Oxidative-mechanical stress signals stem cell niche mediated Lrp5 osteogenesis in eNOS(−/−) null mice. J Cell Biochem. 2012;113:1623–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Hawse JR, Cicek M, Grygo SB, et al. TIEG1/KLF10 modulates Runx2 expression and activity in osteoblasts. PLoS One. 2011;6:e19429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–23.

    Article  CAS  PubMed  Google Scholar 

  36. Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346:1513–21.

    Article  CAS  PubMed  Google Scholar 

  37. Fujino T, Asaba H, Kang MJ, et al. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci U S A. 2003;100:229–34.

    Article  CAS  PubMed  Google Scholar 

  38. Babij P, Zhao W, Small C, et al. High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res. 2003;18:960–74.

    Article  CAS  PubMed  Google Scholar 

  39. Westendorf JJ, Kahler RA, Schroeder TM. Wnt signaling in osteoblasts and bone diseases. Gene. 2004;341:19–39.

    Article  CAS  PubMed  Google Scholar 

  40. Holmen SL, Giambernardi TA, Zylstra CR, et al. Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J Bone Miner Res. 2004;19:2033–40.

    Article  CAS  PubMed  Google Scholar 

  41. Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70:11–9.

    Article  CAS  PubMed  Google Scholar 

  42. Akhter MP, Wells DJ, Short SJ, et al. Bone biomechanical properties in LRP5 mutant mice. Bone. 2004;35:162–9.

    Article  CAS  PubMed  Google Scholar 

  43. Johnson ML, Harnish K, Nusse R, Van Hul W. LRP5 and Wnt signaling: a union made for bone. J Bone Miner Res. 2004;19:1749–57.

    Article  CAS  PubMed  Google Scholar 

  44. Johnson ML, Summerfield DT. Parameters of LRP5 from a structural and molecular perspective. Crit Rev Eukaryot Gene Expr. 2005;15:229–42.

    Article  CAS  PubMed  Google Scholar 

  45. Mani A, Radhakrishnan J, Wang H, et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science (New York, NY). 2007;315:1278–82.

    Article  CAS  Google Scholar 

  46. Kim DH, Inagaki Y, Suzuki T, et al. A new low density lipoprotein receptor related protein, LRP5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein E. J Biochem. 1998;124:1072–6.

    Article  CAS  PubMed  Google Scholar 

  47. Magoori K, Kang MJ, Ito MR, et al. Severe hypercholesterolemia, impaired fat tolerance, and advanced atherosclerosis in mice lacking both low density lipoprotein receptor-related protein 5 and apolipoprotein E. J Biol Chem. 2003;278:11331–6.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Most Sacred Heart of Jesus Cardiology and Valvular Institute, Sheboygan, Wisconsin, USA

    Nalini M. Rajamannan

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  1. Nalini M. Rajamannan
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Rajamannan, N.M. (2018). Osteocardiology: The Atherosclerotic Bone Paradox. In: Osteocardiology. Springer, Cham. https://doi.org/10.1007/978-3-319-64994-8_6

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  • DOI: https://doi.org/10.1007/978-3-319-64994-8_6

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-64993-1

  • Online ISBN: 978-3-319-64994-8

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