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Basic Bone Biology

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Bone Tissue Engineering

Abstract

Bone is a self-renewing, self-healing, composite material. It is organized as a hierarchical/multi-scale structure starting at the molecular level of mineral/collagen/water and scaling up to the structural organ level of a whole bone. The skeleton undergoes constant remodeling, a multicellular process that removes and replaces bone tissue. Bone remodeling is also a central component to bone healing/regeneration. Normal homeostasis and physiological stressors such as healing and regeneration are all made possible by the unique macro/micro/ultrastructure of the skeleton and its interactions with associated cells/tissues. It is only through understanding these basic features and their intricate organization that one can begin to understand the foundation of skeletal tissue engineering.

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References

  1. Burr DB. Bone morphology and organization. In: Burr DB, Allen MR, editors. Basic and applied bone biology. London: Academic Press; 2019. p. 3–26.

    Google Scholar 

  2. Currey JD. How well are bones designed to resist fracture? J Bone Miner Res. 2003;18:591–8.

    PubMed  Google Scholar 

  3. Seeman E. Bone modeling and remodeling. Crit Rev Eukaryot Gene Expr. 2009;19:219–33.

    CAS  PubMed  Google Scholar 

  4. Burr DB. The complex relationship between bone remodeling and the physical and material properties of bone. Osteoporos Int. 2015;26:845–7.

    CAS  PubMed  Google Scholar 

  5. Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem. 2003;88:873–84.

    CAS  PubMed  Google Scholar 

  6. Bellido T, Plotkin LI, Bruzzaniti A. Bone cells. In: Burr DB, Allen MR, editors. Basic and applied bone biology. London: Academic Press; 2019. p. 37–55.

    Google Scholar 

  7. Aubin JE. Mesenchymal stem cells and osteoblast differentiation. In: Principles of bone biology, two-volume set; 2008. p. 85–107.

    Google Scholar 

  8. Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003;4:638–49.

    CAS  PubMed  Google Scholar 

  9. Martin RB. Determinants of the mechanical properties of bones. J Biomech. 1991;24:79–88.

    PubMed  Google Scholar 

  10. Seeman E. Growth and Age-related abnormalities in cortical structure and fracture risk. Endocrinol Metab. 2016;30:419.

    Google Scholar 

  11. Allen MR, Hock JM, Burr DB. Periosteum: biology, regulation, and response to osteoporosis therapies. Bone. 2004;35:1003–12.

    CAS  PubMed  Google Scholar 

  12. Colnot C, Zhang X, Tate MLK. Current insights on the regenerative potential of the periosteum: molecular, cellular, and endogenous engineering approaches. J Orthop Res. 2012;30:1869–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Allen MR. Preclinical models for skeletal research: how commonly used species mimic (or don’t) aspects of human bone. Toxicol Pathol. 2017;45:851–4.

    CAS  PubMed  Google Scholar 

  14. Wagermaier W, Klaushofer K, Fratzl P. Fragility of bone material controlled by internal interfaces. Calcif Tissue Int. 2015;97:201–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Stock SR. The mineral–collagen interface in bone. Calcif Tissue Int. 2015;97:262–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Garnero P. The role of collagen organization on the properties of bone. Calcif Tissue Int. 2015;97:229–40.

    CAS  PubMed  Google Scholar 

  17. Saito M, Marumo K. Effects of collagen crosslinking on bone material properties in health and disease. Calcif Tissue Int. 2015;97:242–61.

    CAS  PubMed  Google Scholar 

  18. Gorski JP. Is all bone the same? Distinctive distributions and properties of non- collagenous matrix proteins in Lamellar vs. Woven bone imply the existence of different underlying osteogenic mechanisms. Crit Rev Oral Biol Med. 1998;9:201–23.

    CAS  PubMed  Google Scholar 

  19. Gorski JP. Biomineralization of bone: a fresh view of the roles of non-collagenous proteins. Front Biosci. 2011;16:2598–621.

    CAS  Google Scholar 

  20. Berendsen A, Olsen B. Bone development Agnes. Bone. 2015;80:14–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Allen MR, Burr DB. Bone growth, modeling, and remodeling. In: Burr DB, Allen MR, editors. Basic and applied bone biology. London: Academic Press; 2019. p. 85–100.

    Google Scholar 

  22. Parfitt AM. Osteonal and hemi‐osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem. 1994;55:273–86.

    CAS  PubMed  Google Scholar 

  23. Newman CL, Allen MR. Bone remodeling. In: Mooren FC, editor. Encyclopedia of exercise medicine in health and disease. Berlin: Springer; 2012. p. 140–3.

    Google Scholar 

  24. Andersen TL, Sondergaard TE, Skorzynska KE, Dagnaes-Hansen F, Plesner TL, Hauge EM, Plesner T, Delaisse JM. A physical mechanism for coupling bone resorption and formation in adult human bone. Am J Pathol. 2009;174:239–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Jensen PR, Andersen TL, Hauge EM, Bollerslev J, Delaissé JM. A joined role of canopy and reversal cells in bone remodeling - lessons from glucocorticoid-induced osteoporosis. Bone. 2015;73:16–23.

    PubMed  Google Scholar 

  26. Matsuo K, Otaki N. Bone cell interactions through Eph/ephrin: bone modeling, remodeling and associated diseases. Cell Adhes Migr. 2012;6:148–56.

    Google Scholar 

  27. Kannus P, Haapasalo H, Sankelo M, Sievänen H, Pasanen M, Heinonen A, Oja P, Vuori I. Effect of starting age of physical activity on bone mass in the dominant arm of tennis and squash players. Ann Intern Med. 1995;123:27–31.

    CAS  PubMed  Google Scholar 

  28. Dempster DW, Zhou H, Recker RR, et al. Remodeling- and modeling-based bone formation with teriparatide versus denosumab: a longitudinal analysis from baseline to 3 months in the AVA study. J Bone Miner Res. 2018;33:298–306.

    CAS  PubMed  Google Scholar 

  29. Bahney CS, Zondervan RL, Allison P, Theologis A, Ashley JW, Ahn J, Miclau T, Marcucio RS, Hankenson KD. Cellular biology of fracture healing. J Orthop Res. 2019;37:35–50.

    PubMed  Google Scholar 

  30. Augat P, Simon U, Liedert A, Claes L. Mechanics and mechano-biology of fracture healing in normal and osteoporotic bone. Osteoporos Int. 2005;16:S36–43.

    PubMed  Google Scholar 

  31. Smith-Adaline EA, Volkman SK, Ignelzi MA Jr, Slade J, Platte S, Goldstein SA. Mechanical environment alters tissue formation patterns during fracture repair. J Orthop Res. 2004;22:1079–85.

    CAS  PubMed  Google Scholar 

  32. Colnot C. Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J Bone Miner Res. 2009;24:274–82.

    PubMed  Google Scholar 

  33. ORelly A, Hankenson KD, Kelly DJ. A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing. Biomech Model Mechanobiol. 2016;15:1279–94.

    Google Scholar 

  34. Yuasa M, Mignemi NA, Nyman JS, et al. Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification. J Clin Invest. 2015;125:3117–31.

    PubMed  PubMed Central  Google Scholar 

  35. Rapp AE, Bindl R, Recknagel S, Erbacher A, Muller I, Schrezenmeier H, Ehrnthaller C, Gebhard F, Ignatius A. Fracture healing is delayed in immunodeficient NOD/scidIL2Rgammacnull mice. PLoS One. 2016;11:e0147465.

    PubMed  PubMed Central  Google Scholar 

  36. Raggatt LJ, Wullschleger ME, Alexander KA, Wu AC, Millard SM, Kaur S, Maugham ML, Gregory LS, Steck R, Pettit AR. Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification. Am J Pathol. 2014;184:3192–204.

    CAS  PubMed  Google Scholar 

  37. Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol. 2012;8:133–43.

    CAS  PubMed  Google Scholar 

  38. Abou-Khalil R, Yang F, Mortreux M, et al. Delayed bone regeneration is linked to chronic inflammation in murine muscular dystrophy. J Bone Miner Res. 2014;29:304–15.

    CAS  PubMed  Google Scholar 

  39. Dishowitz MI, Mutyaba PL, Takacs JD, Barr AM, Engiles JB, Ahn J, Hankenson KD. Systemic inhibition of canonical notch signaling results in sustained callus inflammation and alters multiple phases of fracture healing. PLoS One. 2013;8:e68726.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Könnecke I, Serra A, El Khassawna T, et al. T and B cells participate in bone repair by infiltrating the fracture callus in a two-wave fashion. Bone. 2014;64:155–65.

    PubMed  Google Scholar 

  41. Jiao H, Xiao E, Graves DT. Diabetes and its effect on bone and fracture healing. Curr Osteoporos Rep. 2015;13:327–35.

    PubMed  PubMed Central  Google Scholar 

  42. Toben D, Schroeder I, El Khassawna T, et al. Fracture healing is accelerated in the absence of the adaptive immune system. J Bone Miner Res. 2011;26:113–24.

    CAS  PubMed  Google Scholar 

  43. Lu C, Xing Z, Wang X, Mao J, Marcucio RS, Miclau T. Anti-inflammatory treatment increases angiogenesis during early fracture healing. Arch Orthop Trauma Surg. 2012;132:1205–13.

    PubMed  Google Scholar 

  44. Timmen M, Hidding H, Wieskotter B, Baum W, Pap T, Raschke MJ, Schett G, Zwerina J, Stange R. Influence of antiTNF-alpha antibody treatment on fracture healing under chronic inflammation. BMC Musculoskelet Disord. 2014;15:184.

    PubMed  PubMed Central  Google Scholar 

  45. Josephson AM, Bradaschia-Correa V, Lee S, et al. Age-related inflammation triggers skeletal stem/progenitor cell dysfunction. Proc Natl Acad Sci U S A. 2019;116:6995–7004.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Einhorn TA, Majeska RJ, Rush EB, Levine PM, Horowitz MC. The expression of cytokine activity by fracture callus. J Bone Miner Res. 1995;10:1272–81.

    CAS  PubMed  Google Scholar 

  47. Lu C, Miclau T, Hu D, Marcucio RS. Ischemia leads to delayed union during fracture healing: a mouse model. J Orthop Res. 2007;25:51–61.

    PubMed  PubMed Central  Google Scholar 

  48. Lopas LA, Belkin NS, Mutyaba PL, Gray CF, Hankenson KD, Ahn J. Fractures in geriatric mice show decreased callus expansion and bone volume. Clin Orthop Relat Res. 2014;472:3523–32.

    PubMed  PubMed Central  Google Scholar 

  49. Wang L, Tower RJ, Chandra A, et al. Periosteal mesenchymal progenitor dysfunction and extraskeletally-derived fibrosis contribute to atrophic fracture nonunion. J Bone Miner Res. 2019;34:520–32.

    CAS  PubMed  Google Scholar 

  50. Street J, Bao M, deGuzman L, et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A. 2002;99:9656–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Hankenson KD, Dishowitz M, Gray C, Schenker M. Angiogenesis in bone regeneration. Injury. 2011;42:556–61.

    PubMed  PubMed Central  Google Scholar 

  52. Ogilvie CM, Lu C, Marcucio R, Lee M, Thompson Z, Hu D, Helms JA, Miclau T. Vascular endothelial growth factor improves bone repair in a murine nonunion model. Iowa Orthop J. 2012;32:90–4.

    PubMed  PubMed Central  Google Scholar 

  53. Kawakami Y, Ii M, Matsumoto T, et al. SDF-1/CXCR4 axis in Tie2-lineage cells including endothelial progenitor cells contributes to bone fracture healing. J Bone Miner Res. 2015;30:95–105.

    CAS  PubMed  Google Scholar 

  54. Yellowley C. CXCL12/CXCR4 signaling and other recruitment and homing pathways in fracture repair. Bonekey Rep. 2013;2:300.

    PubMed  PubMed Central  Google Scholar 

  55. Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet. 2006;38:1424–9.

    CAS  PubMed  Google Scholar 

  56. Tsuji K, Cox K, Bandyopadhyay A, Harfe BD, Tabin CJ, Rosen V. BMP4 is dispensable for skeletogenesis and fracture-healing in the limb. J Bone Jt Surg Am. 2008;90(Suppl 1):14–8.

    Google Scholar 

  57. Tsuji K, Cox K, Gamer L, Graf D, Economides A, Rosen V. Conditional deletion of BMP7 from the limb skeleton does not affect bone formation or fracture repair. J Orthop Res. 2010;28:384–9.

    PubMed  PubMed Central  Google Scholar 

  58. Wang C, Inzana JA, Mirando AJ, Ren Y, Liu Z, Shen J, O’Keefe RJ, Awad HA, Hilton MJ. NOTCH signaling in skeletal progenitors is critical for fracture repair. J Clin Invest. 2016;126:1471–81.

    PubMed  PubMed Central  Google Scholar 

  59. Taylor DK, Meganck JA, Terkhorn S, Rajani R, Naik A, O’Keefe RJ, Goldstein SA, Hankenson KD. Thrombospondin-2 influences the proportion of cartilage and bone during fracture healing. J Bone Miner Res. 2009;24:1043–54.

    PubMed  PubMed Central  Google Scholar 

  60. Miclau T, Lu C, Thompson Z, Choi P, Puttlitz C, Marcucio R, Helms JA. Effects of delayed stabilization on fracture healing. J Orthop Res. 2007;25:1552–8.

    PubMed  PubMed Central  Google Scholar 

  61. Alden TD, Pittman DD, Hankins GR, Beres EJ, Engh JA, Das S, Hudson SB, Kerns KM, Kallmes DF, Helm GA. In vivo endochondral bone formation using a bone morphogenetic protein 2 adenoviral vector. Hum Gene Ther. 1999;10:2245–53.

    CAS  PubMed  Google Scholar 

  62. Einhorn TA, Majeska RJ, Mohaideen A, Kagel EM, Bouxsein ML, Lurek TJ, Wozney JM. A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair. J Bone Jt Surg Ser A. 2003;85:1425–35.

    Google Scholar 

  63. Huang Y, Zhang X, Du K, Yang F, Shi Y, Huang J, Tang T, Chen D, Dai K. Inhibition of beta-catenin signaling in chondrocytes induces delayed fracture healing in mice. J Orthop Res. 2012;30:304–10.

    CAS  PubMed  Google Scholar 

  64. Maupin KA, Droscha CJ, Williams BO. A comprehensive overview of skeletal phenotypes associated with alterations in wnt/beta-catenin signaling in humans and mice. Bone Res. 2013;1:27–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Hu DP, Ferro F, Yang F, Taylor AJ, Chang W, Miclau T, Marcucio RS, Bahney CS. Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes. Development. 2017;144:221–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Du X, Xie Y, Xian CJ, Chen L. Role of FGFs/FGFRs in skeletal development and bone regeneration. J Cell Physiol. 2012;227:3731–43.

    CAS  PubMed  Google Scholar 

  67. Williams JN, Kambrath AV, Patel RB, et al. Inhibition of CaMKK2 enhances fracture healing by stimulating Indian hedgehog signaling and accelerating endochondral ossification. J Bone Miner Res. 2018;33:930–44.

    CAS  PubMed  Google Scholar 

  68. Gerstenfeld LC, Cho TJ, Kon T, Aizawa T, Tsay A, Fitch J, Barnes GL, Graves DT, Einhorn TA. Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption. J Bone Miner Res. 2003;18:1584–92.

    CAS  PubMed  Google Scholar 

  69. Chen Y, Whetstone HC, Lin AC, Nadesan P, Wei Q, Poon R, Alman BA. Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing. PLoS Med. 2007;4:1216–29.

    CAS  Google Scholar 

  70. Wang Y, Wan C, Deng L, et al. The hypoxia-inducible factor {alpha} pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest. 2007;117:1616–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Jacobsen KA, Al-Aql ZS, Wan C, et al. Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling. J Bone Miner Res. 2008;23:596–609.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Wagley Y, Chesi A, Acevedo PK, Lu S, Wells AD, Johnson ME, Grant SFA, Hankenson KD. Canonical Notch signaling is required for bone morphogenetic protein-mediated human osteoblast differentiation. Stem Cells. 2020;38:1332. https://doi.org/10.1002/stem.3245.

    Article  CAS  PubMed  Google Scholar 

  73. McArdle A, Marecic O, Tevlin R, Walmsley GG, Chan CK, Longaker MT, Wan DC. The role and regulation of osteoclasts in normal bone homeostasis and in response to injury. Plast Reconstr Surg. 2015;135:808–16.

    CAS  PubMed  Google Scholar 

  74. Gerstenfeld LC, Sacks DJ, Pelis M, Mason ZD, Graves DT, Barrero M, Ominsky MS, Kostenuik PJ, Morgan EF, Einhorn TA. Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res. 2009;24:196–208.

    CAS  PubMed  Google Scholar 

  75. Schmitz JP, Hollinger JO. The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop. 1986:299–308.

    Google Scholar 

  76. Gomes PS, Fernandes MH. Rodent models in bone-related research: the relevance of calvarial defects in the assessment of bone regeneration strategies. Lab Anim. 2011;45:14–24.

    CAS  PubMed  Google Scholar 

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Allen, M.R., Metzger, C.E., Ahn, J., Hankenson, K.D. (2022). Basic Bone Biology. In: Guastaldi, F.P., Mahadik, B. (eds) Bone Tissue Engineering. Springer, Cham. https://doi.org/10.1007/978-3-030-92014-2_2

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