Bone Biology: Development and Regeneration Mechanisms in Physiological and Pathological Conditions

  • Hideki Yoshikawa
  • Noriyuki Tsumaki
  • Akira Myoui


Bone is a highly specialized connective tissue which serves various functions essential for life, such as protection for vital organs including bone marrow, mechanical support as a locomotive organ, metabolic regulation for the minerals, and maintenance of serum homeostasis. Bone development, repair and regeneration are complicatedly regulated by cells, matrix, and local and systemic hormones or cytokines. Understanding the mechanisms of bone development and regeneration is essential for the bone regenerative medicine and bone tissue engineering.

Macroscopic and Microscopic Structure of Bone

There are five types of bones in the human body: long, short, flat, irregular, and sesamoid. Long bones consist of a long shaft (the diaphysis) and two articular surfaces, called epiphyses. The ends of the diaphysis are metaphyses, located in contact with growth plates. Short bones are roughly cube-shaped and have only a thin cortical bone. The bones of the wrist and ankle are short...


Bone Formation Bone Morphogenetic Protein Fracture Healing Bone Tissue Engineering Osteoid Osteoma 
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  1. Akita S et al. (2004) Capillary vessel network integration by inserting a vascular pedicle enhances bone formation in tissue-engineered bone using interconnected porous hydroxyapatite ceramics. Tissue Eng 10:789–795CrossRefGoogle Scholar
  2. Akiyama H et al. (2002) The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 16:2813–2828CrossRefGoogle Scholar
  3. Attisano L, Wrana JL (1998) Mads and Smads in TGFβ signaling. Curr Opin Cell Biol 10:188–194CrossRefGoogle Scholar
  4. Baron R (2003) General principles of bone biology. In: Primer on the metabolic bone diseases and disorders of mineral metabolism, 5th edn. The American Society of Bone and Mineral Research, Washington DC, pp 1–8Google Scholar
  5. Canalis E et al. (1989) Growth factors and the regulation of bone remodeling. J Clin Invest 81:277–281CrossRefGoogle Scholar
  6. Canalis E et al. (2003) Bone morphogenetic proteins, their antagonists and the skeleton. Endocr Rev 24:218–235CrossRefGoogle Scholar
  7. Cho TJ et al. (2003) Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture reapir. J Bone Miner Res 17:513–520CrossRefGoogle Scholar
  8. Derynck, R et al. (1998) Smads: transcriptional activators of TGF-β responses. Cell 95:737–740CrossRefGoogle Scholar
  9. Garland DE (1988) Clinical observations on fractures and heterotopic ossification in the spinal cord and traumatic brain injured populations. Clin Orthop 233:86–101Google Scholar
  10. Gerstenfeld LC, Einhorn TA (2006) Fracture healing: the biology of bone repair and regeneration In: Primer on the metabolic bone diseases and disorders of mineral metabolism, 6th edn, The American Society of Bone and Mineral Research, Washington, DC, pp 42–48Google Scholar
  11. Gerstenfeld LC, Shapiro FD (1996) Expression of bone-specific genes by hypertrophic chondrocytes: Implication of the complex functions of the hypertrophic chondrocyte during endochondral bone development. J Cell Biochem 62:1–9CrossRefGoogle Scholar
  12. Heldin CH et al. (1997) TGF-β signaling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471CrossRefGoogle Scholar
  13. Hill TP et al. (2005) Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8:727–738CrossRefGoogle Scholar
  14. Jones AL et al. (2006) Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg 88A:1431–1441CrossRefGoogle Scholar
  15. Joyce ME et al. (1990) Transforming growth factor-beta and the initiation of chondrogenesis and osteogenesis in the rat femur. J Cell Biol 110:2195–2207CrossRefGoogle Scholar
  16. Kaito T et al. (2005) Potentiation of the activity of bone morphogenetic protein-2 in bone regeneration by a PLA-PEG/hydroxyapatite composite. Biomaterials 26:73–79CrossRefGoogle Scholar
  17. Karaplis AC, Goltzman D (2000) PTH and PTHrP effects on the skeleton. Rev Endocr Metab Disord 1:331–341CrossRefGoogle Scholar
  18. Komori T et al. (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764CrossRefGoogle Scholar
  19. Matsunaga S, Sakou T (2006) OPLL: disease entity, incidence, literature search, and prognosis. In: Yonenobu K et al. (eds) Ossification of the posterior longitudinal ligament, 2nd edn. Springer Tokyo, pp 11–17Google Scholar
  20. Miyamoto S et al. (1992) Ossification of the ligamentum flavum induced by bone morphogenetic protein. An experimental study in mice. J Bone Joint Surg 74B:279–283Google Scholar
  21. Miyazono K et al. (2005) BMP receptor signaling: Transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16:251–263CrossRefGoogle Scholar
  22. Murakami G et al. (2003) Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell 14:2809–2817CrossRefGoogle Scholar
  23. Myoui A et al. (2004) Three-dimensionally engineered hydroxyapatite ceramics with interconnected pores as a bone substitute and tissue engineering scaffold. In: Yaszemski MJ et al. (eds) Biomaterials in Orthopedics. Marcel Dekker, New York, pp 287–300Google Scholar
  24. Nakase T, Yoshikawa H (2006) Potential roles of bone morphogenetic proteins (BMPs) in skeletal repair and regeneration. J Bone Miner Metab 24:425–433CrossRefGoogle Scholar
  25. Nakase T et al. (1994) Transient and localized expression of bone morphogenetic protein 4 messenger RNA during fracture healing. J Bone Miner Res 9:651–659CrossRefGoogle Scholar
  26. Nakashima K et al. (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29CrossRefGoogle Scholar
  27. Nijweide PJ et al. (1996) The osteocyte. In: Bilezikian JP et al. (eds) Principles of bone biology. Academic Press, New York, p 115–126Google Scholar
  28. Noda M, Camilliere JJ (1989) In vivo stimulation of bone formation by transforming growth factor-β. Endocrinology 124:2991–2994CrossRefGoogle Scholar
  29. Okamoto M et al. (2006) Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. J Bone Miner Res 21:1022–1033CrossRefGoogle Scholar
  30. Okuda S et al. (2001) Ossification of the ligamentum flavum associated with osteoblastoma: a report of three cases. Skeletal Radiol 30:402–406CrossRefGoogle Scholar
  31. Ornitz DM, Marie PJ (2002) FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 16:1446–1465CrossRefGoogle Scholar
  32. Phemister DB. (1926) A study of the ossification in bone sarcoma. Radiology 7:17–23Google Scholar
  33. Saito H et al. (1992) Histopathologic and morphometric study of spinal cord lesion in a chronic cord compression model using bone morphogenetic protein in rabbits. Spine 17:1368–1374CrossRefGoogle Scholar
  34. Saito N et al. (2001) Biodegradable poly, -lactic acid–polyethylene glycol block copolymers as a BMP delivery system for inducing bone. J Bone Joint Surg 83A:S92–98Google Scholar
  35. Shafritz AB et al. (1996) Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N Engl J Med 335:555–561CrossRefGoogle Scholar
  36. Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342CrossRefGoogle Scholar
  37. Street J et al. (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A 99:9656–9661CrossRefGoogle Scholar
  38. Takaoka K et al. (1994) Ectopic ossification associated with osteoid osteoma in the acetabulum. A case report. Clin Orthop 299:209–211Google Scholar
  39. Tamai N et al. (2002) Novel hydroxyapatite ceramics with an interconnective porous structure exhibit superior osteoconduction in vivo. J Biomed Mater Res 59:110–117CrossRefGoogle Scholar
  40. Theill LE et al. (2002) RANKL and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 20:795–823CrossRefGoogle Scholar
  41. Tsumaki N, Yoshikawa H (2005) The role of bone morphogenetic proteins in endochondral bone formation. Cytokine Growth Factor Rev 16: 279–285CrossRefGoogle Scholar
  42. Urist MR (1965) Bone: formation by autoinduction. Science 150:893–899CrossRefGoogle Scholar
  43. Urist MR et al. (1979) Growth of osteoid osteoma transplanted into athymic nude mice. Clin Orthop 141:275–280Google Scholar
  44. Vaccaro AR et al. (2005) Comparison of OP-1 Putty (rhBMP-7) to iliac crest autograft for posterolateral lumbar arthrodesis: a minimum 2-year follow-up pilot study. Spine 30:2709–2716CrossRefGoogle Scholar
  45. Vannanen K (1996) Osteoclast function: biology and mechanisms. In: Bilezikian JP et al. (eds) Principles of bone biology. Academic Press, New York, p 103–113Google Scholar
  46. Wozney JM et al. (1988) Novel regulators of bone formation: molecular clones and activities. Science 242:1528–1534CrossRefGoogle Scholar
  47. Yanagita M (2005) BMP antagonists: their roles in development and involvement in pathophysiology. Cytokine Growth Factor Rev 16:309–317CrossRefGoogle Scholar
  48. Yoshida Y et al. (2000) Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 103:1085–1097CrossRefGoogle Scholar
  49. Yoshikawa H, Myoui A (2005) Bone tissue engineering with porous hydroxyapatite ceramics. J Artif Org 8:131–136CrossRefGoogle Scholar
  50. Yoshikawa H et al. (1994a) Periosteal sunburst spiculation in osteosarcoma: a possible role for bone morphogenetic protein. Clin Orthop 308:213–219Google Scholar
  51. Yoshikawa H et al. (1994b) Expression of bone morphogenetic proteins in human osteosarcoma: Immunohistochemical detection with monoclonal antibody. Cancer 73:85–91CrossRefGoogle Scholar
  52. Yoshikawa H et al. (1997) Bone morphogenetic proteins (BMPs) in musculoskeletal oncology. J Musculoskel Res 1:1–12CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Orthopaedic SurgeryOsaka University Graduate School of MedicineJapan

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