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Arthritis und Rheuma 2018; 38(02): 104-112
DOI: 10.1055/s-0038-1649289
Geronto-Orthopädie
Schattauer GmbH

Eigenschaften des Osteozytennetzwerks in gesundem und erkranktem Knochen

Characteristics of the osteocyte network in healthy and diseased human bone
A. vom Scheidt
Institut für Osteologie und Biomechanik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
,
B. Busse
Institut für Osteologie und Biomechanik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
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Publication History



Publication Date:
27 April 2018 (online)

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Zusammenfassung

Humaner Knochen ist von einem komplexen Netzwerk aus Lakunen und Kanalikuli durchzogen, welches von mechanosensitiven Osteozyten bevölkert wird. Durch Signalmoleküle und direkten Zellkontakt regulieren Osteozyten die Aktivität von Osteoblasten und Osteoklasten im Knochenumbau und modulieren so die mechanischen Eigenschaften des Knochens. Zusätzlich greifen Osteozyten in den Kalziumstoffwechsel ein und können lokal Kalzium resorbieren oder eine Mineralisierung beeinflussen. Wir diskutieren zwei Hauptfaktoren, welche die Mechanoresponsivität des Netzwerks schädigen: 1. Der Tod von Osteozyten, z. B. bei unphysiologischer Belastung, und der Mangel an Osteozyten im Alter verschlechtern die Auflösung des mechanosensitiven Netzwerk. Dies verhindert eine adäquate Instandhaltung der Gewebequalität und resultiert in gealtertem, höher mineralisiertem Knochen mit einer Häufung von Mikrorissen. 2. Der Verschluss von Lakunen mit Mineral verhindert zusätzlich den Nährstoffund Signalmolekülfluss im Netzwerk. So wird die Lebensfähigkeit anliegender Zellen behindert und die Mechanoresponsivität verringert. Da die regulierende Funktion der Osteozyten auf den Knochenumbau für eine hohe Fraktur resistenz essenziell ist, bietet sich hier ein großes Potenzial, durch Unterstützung der Osteozytenlebensfähigkeit therapeutisch und präventiv Frakturen zu bekämpfen.

Summary

In bone remodeling the bone-resorbing osteoclasts and bone-forming osteoblasts maintain the mechanical competence of bone in a balanced interaction. Additionally, the osteocyte, the most frequent osseous cell (> 25,000/mm³), resides in lacunae and is connected via channels creating an enormous nanoscale network. Osteocytes have shown exceptional mechanoresponsive and mechanosensitive behavior, allowing them to control bone repair in damaged or aged bone areas and improving the resistance to fracture. Here, we describe the following influences of aging and disease on the osteocyte lacunacanalicular network: - Mineralized lacunae may influence fluid flow and hamper mechanosensitivity, resulting in a loss of mechanical competence. - Further an increasing number of mineralized lacunae, as in aged bone tissue, could make bone more susceptible to fracture. - With a decreasing number of viable osteocytes, the network fails to detect local damages, thereby compromising bone strength. Our article highlights the major role of osteocytes in aging, disease and the preservation of bones’ strength. We found an agingand disease-related decay of the osteocyte-lacunar network to be associated with the loss of bones’ strength. The network decay results in less targeted damage repair, thus enabling increased bone fragility, a major problem in an elderly population. It is essential to unravel the involvement of the osteocyte lacuno-canalicular system in bone fragility to combat fractures with preventive and therapeutic strategies.

Schlüsselwörter

Osteozytennetzwerk - Knochenumbau - Alterseinfluss - Osteoporose

Keywords

Osteocyte network - bone remodeling - aging - osteoporosis
 

  • Literatur

  • 1 Kanis JA, Odén A, McCloskey EV. et al. A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporos Int 2012; 23 (09) 2239-2256.
    CrossrefPubMedGoogle Scholar
  • 2 Cooper C, Campion G, Melton LJ. Hip fractures in the elderly: A world-wide projection. Osteoporos Int 1992; 02 (06) 285-289.
    CrossrefPubMedGoogle Scholar
  • 3 Milovanovic P, Zimmermann EA, Riedel C. et al. Multi-level characterization of human femoral cortices and their underlying osteocyte network reveal trends in quality of young, aged, osteoporotic and antiresorptive-treated bone. Biomaterials 2015; 45: 46-55 [Epub 2015/02/11].
    CrossrefPubMedGoogle Scholar
  • 4 Launey ME, Buehler MJ, Ritchie RO. On the mechanistic origins of toughness in bone. Annu Rev Mater Res 2010; 40 (01) 25-53.
    CrossrefGoogle Scholar
  • 5 Zimmermann EA, Kohne T, Bale HA. et al. Modifications to Nanoand Microstructural Quality and the Effects on Mechanical Integrity in Paget’s Disease of Bone. J Bone Miner Res 2015; 30 (02) 264-273.
    CrossrefPubMedGoogle Scholar
  • 6 Seeman E. Mineral Homeostasis. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism: West Sussex, GB: John Wiley & Sons, Inc 2013; 171-172.
    Google Scholar
  • 7 Currey JD. Bones: structure and mechanics. Princeton, N. J: Princeton University Press; 2002
    Google Scholar
  • 8 Busse B, Bale HA, Zimmermann EA. et al. Vitamin d deficiency induces early signs of aging in human bone, increasing the risk of fracture. Sci Transl Med 2013; 05 (193) 193ra88 [Epub 2013/07/12]..
    CrossrefPubMedGoogle Scholar
  • 9 Busse B, Hahn M, Schinke T. et al. Reorganization of the femoral cortex due to age-, sex-, and endoprosthetic-related effects emphasized by osteonal dimensions and remodeling. J Biomed Mater Res A 2010; 92 (04) 1440-1451 [Epub 2009/04/11].
    PubMedGoogle Scholar
  • 10 Busse B, Jobke B, Hahn M. et al. Effects of strontium ranelate administration on bisphosphonatealtered hydroxyapatite: Matrix incorporation of strontium is accompanied by changes in mineralization and microstructure. Acta Biomater 2010; 06 (12) 4513-4521 [Epub 2010/07/27].
    CrossrefPubMedGoogle Scholar
  • 11 Busse B, Djonic D, Milovanovic P. et al. Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone. Aging Cell 2010; 09 (06) 1065-1075 [Epub 2010/09/30].
    CrossrefPubMedGoogle Scholar
  • 12 Milovanovic P, Zimmermann EA, Hahn M. et al. Osteocytic Canalicular Networks: Morphological Implications for Altered Mechanosensitivity. ACS Nano 2013; 07 (09) 7542-7551 [Epub 2013/08/06].
    CrossrefPubMedGoogle Scholar
  • 13 Noble BS, Reeve J. Osteocyte function, osteocyte death and bone fracture resistance. Mol Cell Endocrinol 2000; 159 (1-2): 7-13.
    CrossrefPubMedGoogle Scholar
  • 14 Turner C. Skeletal Adaptation to Mechanical Loading. Clin Rev Bone Miner Metab 2007; 05 (04) 181-194.
    CrossrefGoogle Scholar
  • 15 Wysolmerski JJ. Osteocytes remove and replace perilacunar mineral during reproductive cycles. Bone 2013; 54 (02) 230-236.
    CrossrefPubMedGoogle Scholar
  • 16 Taylor D, Hazenberg JG, Lee TC. Living with cracks: Damage and repair in human bone. Nat Mater 2007; 06 (04) 263-268.
    CrossrefPubMedGoogle Scholar
  • 17 Klein-Nulend J, van der Plas A, Semeins C. et al. Sensitivity of osteocytes to biomechanical stress in vitro. FASEB J 1995; 09 (05) 441-445.
    CrossrefPubMedGoogle Scholar
  • 18 Adachi T, Aonuma Y, Tanaka M. et al. Calcium response in single osteocytes to locally applied mechanical stimulus: Differences in cell process and cell body. J Biomech 2009; 42 (12) 1989-1995.
    CrossrefPubMedGoogle Scholar
  • 19 Turner CH, Forwood MR. What role does the osteocyte network play in bone adaptation?. Bone 1995; 16 (03) 283-285.
    CrossrefPubMedGoogle Scholar
  • 20 Tan SD, de Vries TJ, Kuijpers-Jagtman AM. et al. Osteocytes subjected to fluid flow inhibit osteoclast formation and bone resorption. Bone 2007; 41 (05) 745-751.
    CrossrefPubMedGoogle Scholar
  • 21 Kulkarni R, Bakker A, Everts V, Klein-Nulend J. Inhibition of Osteoclastogenesis by Mechanically Loaded Osteocytes: Involvement of MEPE. Calcif Tissue Int 2010; 87 (05) 461-468.
    CrossrefPubMedGoogle Scholar
  • 22 Vezeridis PS, Semeins CM, Chen Q, Klein-Nulend J. Osteocytes subjected to pulsating fluid flow regulate osteoblast proliferation and differentiation. Biochem Biophys Res Commun 2006; 348 (03) 1082-1088.
    CrossrefPubMedGoogle Scholar
  • 23 McGarry JG, Klein-Nulend J, Mullender MG, Prendergast PJ. A comparison of strain and fluid shear stress in stimulating bone cell responses - a computational and experimental study. FASEB J 2005; 19 (03) 482-484.
    CrossrefPubMedGoogle Scholar
  • 24 Turner CH, Owan I, Jacob DS. et al. Effects of nitric oxide synthase inhibitors on bone formation in rats. Bone 1997; 21 (06) 487-490.
    CrossrefPubMedGoogle Scholar
  • 25 Tan SD, Bakker AD, Semeins CM. et al. Inhibition of osteocyte apoptosis by fluid flow is mediated by nitric oxide. Biochem Biophys Res Commun 2008; 369 (04) 1150-1154.
    CrossrefPubMedGoogle Scholar
  • 26 Da Costa TMGómez, Barrett JG, Sample SJ. et al. Up-regulation of site-specific remodeling without accumulation of microcracking and loss of osteocytes. Bone 2005; 37 (01) 16-24.
    CrossrefPubMedGoogle Scholar
  • 27 Boyde A. The real response of bone to exercise. J Anat 2003; 203 (02) 173-189.
    CrossrefPubMedGoogle Scholar
  • 28 Noble B. Bone microdamage and cell apoptosis. Eur Cell Mater 2003; 06: 46-55 [Epub 2004/01/08].
    Google Scholar
  • 29 Dooley C, Tisbo P, Lee T, Taylor D. Rupture of osteocyte processes across microcracks: the effect of crack length and stress. Biomech Model Mechanobiol 2012; 11 (06) 759-766.
    CrossrefPubMedGoogle Scholar
  • 30 Taylor D, Mulcahy L, Presbitero G. et al. The Scissors Model of Microcrack Detection in Bone: Work in Progress. MRS Online Proceedings Library 2010; 1274.
    Google Scholar
  • 31 Hazenberg J, Taylor D, Lee T. The role of osteocytes and bone microstructure in preventing osteoporotic fractures. Osteoporos Int 2007; 18 (01) 1-8.
    PubMedGoogle Scholar
  • 32 Heino TJ, Kurata K, Higaki H, Väänänen HK. Evidence for the role of osteocytes in the initiation of targeted remodeling. Technol Health Care 2009; 17 (01) 49-56.
    PubMedGoogle Scholar
  • 33 Cardoso L, Herman BC, Verborgt O. et al. Osteocyte Apoptosis Controls Activation of Intracortical Resorption in Response to Bone Fatigue. J Bone Miner Res 2009; 24 (04) 597-605.
    CrossrefPubMedGoogle Scholar
  • 34 Henriksen K, Neutzsky-Wulff AV, Bonewald LF, Karsdal MA. Local communication on and within bone controls bone remodeling. Bone 2009; 44 (06) 1026-1033.
    CrossrefPubMedGoogle Scholar
  • 35 Regelsberger J, Milovanovic P, Schmidt T. et al. Changes to the cell, tissue and architecture levels in cranial suture synostosis reveal a problem of timing in bone development. Eur Cell Mater 2012; 24: 441-458 [Epub 2012/11/29].
    PubMedGoogle Scholar
  • 36 Lloyd S, Loiselle A, Zhang Y, Donahue H. Evidence for the role of connexin 43-mediated intercellular communication in the process of intracortical bone resorption via osteocytic osteolysis. BMC Musculoskeletal Disorders 2014; 15 (01) 122.
    CrossrefPubMedGoogle Scholar
  • 37 Teti A, Zallone A. Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. Bone 2009; 44 (01) 11-16.
    CrossrefPubMedGoogle Scholar
  • 38 Bonewald LF. The amazing osteocyte. J Bone Miner Res 2011; 26 (02) 229-238.
    CrossrefPubMedGoogle Scholar
  • 39 Thompson WR, Modla S, Grindel BJ. et al. Perlecan/Hspg2 deficiency alters the pericellular space of the lacunocanalicular system surrounding osteocytic processes in cortical bone. J Bone Miner Res 2011; 26 (03) 618-629.
    CrossrefPubMedGoogle Scholar
  • 40 You L-D, Weinbaum S, Cowin SC, Schaffler MB. Ultrastructure of the osteocyte process and its pericellular matrix. Anat Rec A 2004; 278A (02) 505-513.
    CrossrefPubMedGoogle Scholar
  • 41 Fritton SP, Weinbaum S. Fluid and Solute Transport in Bone: Flow-Induced Mechanotransduction. Annu Rev Fluid Mech 2008; 41 (01) 347-374.
    Google Scholar
  • 42 Tang SY, Herber R-P, Ho SP, Alliston T. Matrix metalloproteinase-13 is required for osteocytic perilacunar remodeling and maintains bone fracture resistance. J Bone Miner Res 2012; 27 (09) 1936-1950.
    CrossrefPubMedGoogle Scholar
  • 43 Holmbeck K, Bianco P, Pidoux I. et al. The metalloproteinase MT1-MMP is required for normal development and maintenance of osteocyte processes in bone. J Cell Sci 2005; 118 (01) 147-156.
    CrossrefPubMedGoogle Scholar
  • 44 Eidelman N, Chow L, Brown W. Calcium phosphate saturation levels in ultrafiltered serum. Calcif Tissue Int 1987; 40 (02) 71-78.
    CrossrefPubMedGoogle Scholar
  • 45 Price PA, Lim JE. The Inhibition of Calcium Phosphate Precipitation by Fetuin Is Accompanied by the Formation of a Fetuin-Mineral Complex. J Biol Chem 2003; 278 (24) 22144-22152.
    CrossrefPubMedGoogle Scholar
  • 46 Parfitt AM. Life history of osteocytes: relationship to bone age, bone remodeling, and bone fragility. J Musculoskelet Neuronal Interact 2002; 02 (06) 499-500 [Epub 2005/03/11].
    Google Scholar
  • 47 Seeman E. Ageand Menopause-Related Bone Loss Compromise Cortical and Trabecular Microstructure. J Gerontol A Biol Sci Med Sci 2013; 68 (10) 1218-1225.
    CrossrefPubMedGoogle Scholar
  • 48 Busse B, Hahn M, Soltau M. et al. Increased calcium content and inhomogeneity of mineralization render bone toughness in osteoporosis: mineralization, morphology and biomechanics of human single trabeculae. Bone 2009; 45 (06) 1034-1043 [Epub 2009/08/15].
    CrossrefPubMedGoogle Scholar
  • 49 Manolagas SC, Parfitt AM. What old means to bone. Trends Endocrinol Metabol 2010; 21 (06) 369-374.
    Google Scholar
  • 50 Frost HM. In Vivo Osteocyte Death. J Bone Joint Surg Am 1960; 42 (01) 138-143.
    CrossrefPubMedGoogle Scholar
  • 51 Tomkinson A, Gevers EF, Wit JM. et al. The Role of Estrogen in the Control of Rat Osteocyte Apoptosis. J Bone Miner Res 1998; 13 (08) 1243-1250.
    CrossrefPubMedGoogle Scholar
  • 52 O’Brien CA, Jia D, Plotkin LI. et al. Glucocorticoids Act Directly on Osteoblasts and Osteocytes to Induce Their Apoptosis and Reduce Bone Formation and Strength. Endocrinol 2004; 145 (04) 1835-1841.
    CrossrefPubMedGoogle Scholar
  • 53 Frost HM. Micropetrosis. J Bone Joint Surg Am 1960; 42: 144-150.
    CrossrefPubMedGoogle Scholar
  • 54 Aguirre JI, Plotkin LI, Stewart SA. et al. Osteocyte Apoptosis Is Induced by Weightlessness in Mice and Precedes Osteoclast Recruitment and Bone Loss. J Bone Miner Res 2006; 21 (04) 605-615.
    CrossrefPubMedGoogle Scholar
  • 55 Noble BS, Peet N, Stevens HY. et al. Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. Am J Phys Cell Physiol 2003; 284 (04) C934-C943.
    Google Scholar
  • 56 Kitase Y, Barragan L, Qing H. et al. Mechanical induction of PGE2 in osteocytes blocks glucocorticoid-induced apoptosis through both the β-catenin and PKA pathways. J Bone Miner Res 2010; 25 (12) 2657-2668.
    CrossrefPubMedGoogle Scholar
  • 57 Knothe MTate, Steck R, Forwood M, Niederer P. In vivo demonstration of load-induced fluid flow in the rat tibia and its potential implications for processes associated with functional adaptation. J Exp Biol 2000; 203 (18) 2737-2745.
    PubMedGoogle Scholar
  • 58 Boyde A, Hendel P, Hendel R. et al. Human cranial bone structure and the healing of cranial bone grafts: a study using backscattered electron imaging and confocal microscopy. Anat Embriol 1990; 181 (03) 235-251.
    PubMedGoogle Scholar
  • 59 Kingsmill VJ, Boyde A. Mineralisation density of human mandibular bone: quantitative backscattered electron image analysis. J Anat 1998; 192 (02) 245-256.
    CrossrefPubMedGoogle Scholar
  • 60 Carpentier VT, Wong J, Yeap Y. et al. Increased proportion of hypermineralized osteocyte lacunae in osteoporotic and osteoarthritic human trabecular bone: Implications for bone remodeling. Bone 2012; 50 (03) 688-694.
    CrossrefPubMedGoogle Scholar
  • 61 Bell LS, Kayser M, Jones C. The mineralized osteocyte: A living fossil. Am J Phys Anthropol 2008; 137 (04) 449-456.
    CrossrefPubMedGoogle Scholar
  • 62 Belanger LF, Jarry L, Uhthoff HK. Osteocytic Osteolysis in Pagets Disease. Rev Can Biol Exptl 1968; 27 (01) 37-44.
    Google Scholar
  • 63 Milovanovic P, Rakocevic Z, Djonic D. et al. Nanostructural, compositional and micro-architectural signs of cortical bone fragility at the superolateral femoral neck in elderly hip fracture patients vs. healthy aged controls. Experimental Gerontology 2014; 55: 19-28.
    CrossrefPubMedGoogle Scholar
  • 64 Bernhard A, Milovanovic P, Zimmermann EA. et al. Micro-morphological properties of osteons reveal changes in cortical bone stability during aging, osteoporosis, and bisphosphonate treatment in women. Osteoporos Int 2013; 24 (10) 2671-2680 [Epub 2013/05/02].
    CrossrefPubMedGoogle Scholar
  • 65 Bellido T, Plotkin LI. Novel actions of bisphosphonates in bone: Preservation of osteoblast and osteocyte viability. Bone 2011; 49 (01) 50-55.
    CrossrefPubMedGoogle Scholar
  • 66 Plotkin LI, Lezcano V, Thostenson J. et al. Connexin 43 Is Required for the Anti-Apoptotic Effect of Bisphosphonates on Osteocytes and Osteoblasts In Vivo. J Bone Miner Res 2008; 23 (11) 1712-1721.
    CrossrefPubMedGoogle Scholar
  • 67 Schaffler M, Cheung W-Y, Majeska R, Kennedy O. Osteocytes: Master Orchestrators of Bone. Calcif Tissue Int 2014; 94 (01) 5-24.
    CrossrefPubMedGoogle Scholar
  • 68 Jan GH, Michael F, Eilis F. et al. Microdamage: A cell transducing mechanism based on ruptured osteocyte processes. J Biomech 2006; 39 (11) 2096-2103.
    CrossrefPubMedGoogle Scholar
  • 69 Weinbaum S, Cowin SC, Zeng Y. A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses. J Biomech 1994; 27 (03) 339-360.
    CrossrefPubMedGoogle Scholar
  • 70 Knothe MLTate. “Whither flows the fluid in bone?” An osteocyte’s perspective. J Biomech 2003; 36 (10) 1409-1424.
    CrossrefPubMedGoogle Scholar