3
Bone remodelling: its local regulation and the emergence of bone fragility

https://doi.org/10.1016/j.beem.2008.07.006Get rights and content

Bone modelling prevents the occurrence of damage by adapting bone structure – and hence bone strength – to its loading circumstances. Bone remodelling removes damage, when it inevitably occurs, in order to maintain bone strength. This cellular machinery is successful during growth, but fails during advancing age because of the development of a negative balance between the volumes of bone resorbed and formed during remodelling by the basic multicellular unit (BMU), high rates of remodelling during midlife in women and late in life in both sexes, and a decline in periosteal bone formation. together resulting in bone loss and structural decay each time a remodelling event occurs. The two steps in remodelling – resorption of a volume of bone by osteoclasts and formation of a comparable volume by osteoblasts – are sequential, but the regulatory events leading to these two fully differentiated functions are not. Reparative remodelling is initiated by damage producing osteocyte apoptosis, which signals the location of damage via the osteocyte canalicular system to endosteal lining cells which forms the canopy of a bone-remodelling compartment (BRC). Within the BRC, local recruitment of osteoblast precursors from the lining cells, the marrow and circulation, direct contact with osteoclast precursors, osteoclastogenesis and molecular cross-talk between precursors, mature cells, cells of the immune system, and products of the resorbed matrix, titrate the birth, work and lifespan of the cells of this multicellular remodelling machinery to either remove or form a net volume of bone appropriate to the mechanical requirements.

Section snippets

Bone modelling and remodelling

The material composition and structure of bone determine the loads it can tolerate.1 While this is self-evident, the converse – that the loads on bone determine its structure – is less evident. Adaptation of the material composition and structure of bone to prevailing loads is carried out by the cellular machinery of bone modelling and remodelling.2 Bone modelling and remodelling optimize bone strength and minimize mass, serving the needs of strength for loading and lightness for mobility. Bone

Cellular and molecular events in bone remodelling

While resorption of a volume of bone by osteoclasts precedes formation of a comparable volume of bone by osteoblasts5, these sequential functions are probably regulated by cellular and molecular events that are contemporaneous and multidirectional. Bone remodelling is tightly regulated by central, systemic and local factors that provide signals to and between the members of this multicellular unit. The osteoblasts and osteoclasts are the executive cells of the BMU, but this multicellular unit

Aging and changes in the remodelling machinery leading to bone loss and structural decay

There are at least four age-related changes in the cellular machinery of bone modelling and remodelling that compromise the material and structural properties of bone.116 Remodelling rate is rapid during growth, because each remodelling event deposits only a small amount of bone.9 As growth nears its ‘programmed’ completion, rapid remodelling is no longer needed, and the remodelling rate slows. With the completion of longitudinal growth, the only requirement for bone formation is the repair of

Summary and conclusion

Adaptive and reparative bone remodelling may be initiated from signals by the osteocyte to the bone lining cell. In adaptive modelling, bone formation occurs without resorption altering the size and shape of bone, while bone resorption during growth without bone formation is also bone modelling and excavates the marrow cavity. Bone remodelling, the resorption of bone followed by focal bone formation by the BMU, is carried out by actively resorbing osteoclasts, generated through the action of

Acknowledgements

Work from the authors' laboratories is supported by NHMRC Program (TJM) and Project (ES) grants.

References (160)

  • C. Zhao et al.

    Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis

    Cell Metabolism

    (2006)
  • E.B. Pasquale

    Eph-ephrin bidirectional signaling in physiology and disease

    Cell

    (2008)
  • D. Heymann et al.

    gp130 Cytokine family and bone cells

    Cytokine

    (2000)
  • M.A. Karsdal et al.

    Osteoclasts secrete non-bone derived signals that induce bone formation

    Biochemical and Biophysical Research Communications

    (2008)
  • T.J. Martin et al.

    Osteoclast-derived activity in the coupling of bone formation to resorption

    Trends in Molecular Medicine

    (2005)
  • N. Amizuka et al.

    Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development

    Developmental Biology

    (1996)
  • J. Mao et al.

    Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway

    Molecular Cell

    (2001)
  • Y. Gong et al.

    LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development

    Cell

    (2001)
  • J. Li et al.

    Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia

    Bone

    (2006)
  • H. Zhou et al.

    Osteoblasts directly control lineage commitment of mesenchymal progenitor cells through Wnt signaling

    Journal of Biological Chemistry

    (2008)
  • P.V. Hauschka et al.

    Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose

    Journal of Biological Chemistry

    (1986)
  • G.A. Rodan

    Introduction to bone biology

    Bone

    (1992)
  • S. Vukicevic et al.

    Localization of osteogenic protein-1 (bone morphogenetic protein-7) during human embryonic development: high affinity binding to basement membranes

    Biochemical and Biophysical Research Communications

    (1994)
  • S. Vukicevic et al.

    Autoradiographic localization of osteogenin binding sites in cartilage and bone during rat embryonic development

    Developmental Biology

    (1990)
  • E.M. Spencer et al.

    In vivo actions of insulin-like growth factor-I (IGF-I) on bone formation and resorption in rats

    Bone

    (1991)
  • Currey J Bones

    Structure and Mechanics

    (2002)
  • A.M. Parfitt

    Skeletal heterogeneity and the purposes of bone remodelling: implications for the understanding of osteoporosis

  • P.D.F. Murray et al.

    Self differentiation in the grafted limb bud of the chick

    Journal of Anatomy

    (1925)
  • R. Hattner et al.

    Suggested sequential mode of control of changes in cell behaviour in adult bone remodelling

    Nature

    (1965)
  • F. Rauch et al.

    The development of metaphyseal cortex – implications for distal radius fractures during growth

    Journal of Bone and Mineral Research

    (2001)
  • E.S. Orwoll

    Toward an expanded understanding of the role of the periosteum in skeletal health

    Journal of Bone and Mineral Research

    (2003)
  • T. Mashiba et al.

    Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib

    Journal of Bone and Mineral Research

    (2000)
  • C.V. Odvina et al.

    Severely suppressed bone turnover: a potential complication of alendronate therapy

    The Journal of Clinical Endocrinology and Metabolism

    (2005)
  • G. Marotti et al.

    Structure-function relationships in the osteocyte

    Italian Journal of Mineral and Electrolyte Metabolism

    (1990)
  • S.C. Manolagas

    Choreography from the tomb; an emerging role of dying osteocytes in the purposeful, not so purposeful targeting of bone remodeling

    BoneKey Osteovision

    (2006)
  • N.E. Lane et al.

    Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice

    Journal of Bone and Mineral Research

    (2006)
  • C.A. O'Brien et al.

    Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength

    Endocrinology

    (2004)
  • O. Verborgt et al.

    Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo

    Journal of Bone and Mineral Research

    (2000)
  • D. Taylor

    Bone maintenance and remodeling: a control system based on fatigue damage

    Journal of Orthopaedic Research

    (1997)
  • W.D. Clark et al.

    Osteocyte apoptosis and osteoclast presence in chicken radii 0-4 days following osteotomy

    Calcified Tissue International

    (2005)
  • J.I. Aguirre et al.

    Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss

    Journal of Bone and Mineral Research

    (2006)
  • E.M. Hauge et al.

    Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers

    Journal of Bone and Mineral Research

    (2001)
  • T.J. Chambers et al.

    Mammalian collagenase predisposes bone surfaces to osteoclastic resorption

    Cell and Tissue Research

    (1985)
  • T.J. Chambers et al.

    Bone cells predispose bone surfaces to resorption by exposure of mineral to osteoclastic contact

    Journal of Cell Science

    (1985)
  • K. Fuller et al.

    Localisation of mRNA for collagenase in osteocytic, bone surface and chondrocytic cells but not osteoclasts

    Journal of Cell Science

    (1995)
  • N.C. Partridge et al.

    Hormonal regulation of the production of collagenase and a collagenase inhibitor activity by rat osteogenic sarcoma cells

    Endocrinology

    (1987)
  • R. Chiusaroli et al.

    Collagenase cleavage of type I collagen is essential for both basal and parathyroid hormone (PTH)/PTH-related peptide receptor-induced osteoclast activation and has differential effects on discrete bone compartments

    Endocrinology

    (2003)
  • T.J. Chambers

    Osteoblasts release osteoclasts from calcitonin-induced quiescence

    Journal of Cell Science

    (1982)
  • G.A. Rodan et al.

    Role of osteoblasts in hormonal control of bone resorption – a hypothesis

    Calcified Tissue International

    (1981)
  • A.M. Parfitt

    The bone remodeling compartment: a circulatory function for bone lining cells

    Journal of Bone and Mineral Research

    (2001)
  • Cited by (145)

    • Current use of bone turnover markers in the management of osteoporosis

      2022, Clinical Biochemistry
      Citation Excerpt :

      Cancellous bone provides strength to the skeleton due to its architecture without adding too much weight and is also metabolically more active due to the larger surface area. The adult bone is continuously being remodelled in order to repair microdamage, preserve bone strength and mechanical competence as well as maintain calcium homeostasis [3]. Remodelling is a surface phenomenon and occurs focally in bone remodelling units (BRU) with parathyroid hormone (PTH), as well as cell signalling molecules such as osteoprotegerin and Receptor Activator of Nuclear κ B ligand (RANK-L) being major regulators of this process.

    • Co-encapsulation of combinatorial flavonoids in biodegradable polymeric nanoparticles for improved anti-osteoporotic activity in ovariectomized rats

      2021, Environmental Technology and Innovation
      Citation Excerpt :

      Remodelling and maintenance of bone requires a coordinated balance between osteoclast which causes resorption of bone and osteoblasts that causes formation of bone (Martin and Seeman, 2008; Ming et al., 2013).

    • Post-natal bone physiology

      2020, Seminars in Fetal and Neonatal Medicine
      Citation Excerpt :

      Siddiqui and Partridge [46] reviewed the role of cytokines in osteoclast development and reported that interleukins-1 (IL-1), IL-6 and tumor necrosis factor (TNF) stimulate osteoclast development, while IL-4, IL-18, and interferon- γ inhibit osteoclast development. Post-natal bone remodeling is a dynamic process of balancing osteoclast-mediated bone resorption and osteoblast-mediated bone formation, with the skeletal responses to changes in loading and physiologic needs is met to ensure mineral homeostasis [47]. Remodeling is initiated by stimulation of osteoclast formation, followed by osteoclast-mediated bone resorption which takes few weeks, a reversal period, lag time between the end of resorption and the beginning of formation it takes four or five weeks, and then a long period of bone matrix formation and mineralization mediated by osteoblasts which takes 3–4 months for one packet (Fig. 1).

    View all citing articles on Scopus
    View full text