Skip to main content

Advertisement

SpringerLink
Log in

Osteoclasts prefer aged bone

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

We investigated whether the age of the bones endogenously exerts control over the bone resorption ability of the osteoclasts, and found that osteoclasts preferentially develop and resorb bone on aged bone. These findings indicate that the bone matrix itself plays a role in targeted remodeling of aged bones.

Introduction

Osteoclasts resorb aging bone in order to repair damage and maintain the quality of bone. The mechanism behind the targeting of aged bone for remodeling is not clear. We investigated whether bones endogenously possess the ability to control osteoclastic resorption.

Methods

To biochemically distinguish aged and young bones; we measured the ratio between the age-isomerized βCTX fragment and the non-isomerized αCTX fragment. By measurement of TRACP activity, CTX release, number of TRACP positive cells and pit area/pit number, we evaluated osteoclastogenesis as well as osteoclast resorption on aged and young bones.

Results

We found that the αCTX / βCTX ratio is 3:1 in young compared to aged bones, and we found that both α and βCTX are released by osteoclasts during resorption. Osteoclastogenesis was augmented on aged compared to young bones, and the difference was enhanced under low serum conditions. We found that mature osteoclasts resorb more on aged than on young bone, despite unchanged adhesion and morphology.

Conclusions

These data indicate that the age of the bone plays an important role in controlling osteoclast-mediated resorption, with significantly higher levels of osteoclast differentiation and resorption on aged bones when compared to young bones.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Frost HM (1969) Tetracycline-based histological analysis of bone remodeling. Calcif Tissue Res 3:211–237

    Article  PubMed  CAS  Google Scholar 

  2. Parfitt AM (2002) Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression. Bone 30:5–7

    Article  PubMed  CAS  Google Scholar 

  3. Han ZH, Palnitkar S, Rao DS et al (1997) Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: implications for mechanisms of bone loss. J Bone Miner Res 12:498–508

    Article  PubMed  CAS  Google Scholar 

  4. Burr DB, Martin RB (1993) Calculating the probability that microcracks initiate resorption spaces. J Biomech 26:613–616

    Article  PubMed  CAS  Google Scholar 

  5. Noble B (2003) Bone microdamage and cell apoptosis. Eur Cell Mater 6:46–55

    PubMed  CAS  Google Scholar 

  6. Burr DB (2002) Targeted and nontargeted remodeling. Bone 30:2–4

    Article  PubMed  CAS  Google Scholar 

  7. Heaney RP (2003) Is the paradigm shifting? Bone 33:457–465

    Article  PubMed  Google Scholar 

  8. Chan GK, Duque G (2002) Age-related bone loss: old bone, new facts. Gerontology 48:62–71

    Article  PubMed  Google Scholar 

  9. Fledelius C, Johnsen AH, Cloos PA et al (1997) Characterization of urinary degradation products derived from type I collagen. Identification of a beta-isomerized Asp-Gly sequence within the C-terminal telopeptide (alpha1) region. J Biol Chem 272:9755–9763

    Article  PubMed  CAS  Google Scholar 

  10. Cloos PA, Lyubimova N, Solberg H et al (2004) An immunoassay for measuring fragments of newly synthesized collagen type I produced during metastatic invasion of bone. Clin Lab 50:279–289

    PubMed  CAS  Google Scholar 

  11. Cloos PA, Fledelius C (2000) Collagen fragments in urine derived from bone resorption are highly racemized and isomerized: a biological clock of protein aging with clinical potential. Biochem J 345(Pt 3):473–480

    Article  PubMed  CAS  Google Scholar 

  12. Currey JD, Brear K, Zioupos P (1996) The effects of ageing and changes in mineral content in degrading the toughness of human femora. J Biomech 29:257–260

    Article  PubMed  CAS  Google Scholar 

  13. Dickson IR, Bagga MK (1985) Changes with age in the non-collagenous proteins of human bone. Connect. Tissue Res 14:77–85

    PubMed  CAS  Google Scholar 

  14. Triffitt JT (1976) Plasma proteins present in human cortical bone: enrichment of the alpha2HS-glycoprotein. Calcif Tissue Res 22:27–33

    PubMed  CAS  Google Scholar 

  15. Fedarko NS, Vetter UK, Weinstein S et al (1992) Age-related changes in hyaluronan, proteoglycan, collagen, and osteonectin synthesis by human bone cells. J Cell Physiol 151:215–227

    Article  PubMed  CAS  Google Scholar 

  16. Perkins SL, Gibbons R, Kling S et al (1994) Age-related bone loss in mice is associated with an increased osteoclast progenitor pool. Bone 15:65–72

    Article  PubMed  CAS  Google Scholar 

  17. Noble BS, Stevens H, Loveridge N et al (1997) Identification of apoptotic changes in osteocytes in normal and pathological human bone. Bone 20:273–282

    Article  PubMed  CAS  Google Scholar 

  18. Bonewald LF (2002) Osteocytes: a proposed multifunctional bone cell. J Musculoskelet Neuronal Interact 2:239–241

    PubMed  CAS  Google Scholar 

  19. Noble BS, Peet N, Stevens HY et al (2003) Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. Am J Physiol Cell Physiol 284:C934–C943

    PubMed  CAS  Google Scholar 

  20. Cao J, Venton L, Sakata T et al (2003) Expression of RANKL and OPG correlates with age-related bone loss in male C57BL/6 mice. J Bone Miner Res 18:270–277

    Article  PubMed  CAS  Google Scholar 

  21. Ueland T, Brixen K, Mosekilde L et al (2003) Age-related changes in cortical bone content of insulin-like growth factor binding protein (IGFBP)-3, IGFBP-5, osteoprotegerin, and calcium in postmenopausal osteoporosis: a cross-sectional study. J Clin Endocrinol Metab 88:1014–1018; 2003

    Article  PubMed  CAS  Google Scholar 

  22. Karsdal MA, Hjorth P, Henriksen K et al (2003) TGF-beta controls human osteoclastogenesis through the p38 MAP kinase and regulation of RANK expression. J Biol Chem 278:44975–44987

    Article  PubMed  CAS  Google Scholar 

  23. Henriksen K, Gram J, Schaller S et al (2004) Characterization of osteoclasts from patients harboring a G215R mutation in ClC-7 causing autosomal dominant osteopetrosis type II. Am J Pathol 164:1537–1545

    PubMed  CAS  Google Scholar 

  24. Schaller S, Henriksen K, Sveigaard C et al (2004) The chloride channel inhibitor n53736 prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res 19:1144–1153

    Article  PubMed  CAS  Google Scholar 

  25. Henriksen K, Gram J, Hoegh-Andersen P et al (2005) Osteoclasts from patients with Autosomal Dominant Osteopetrosis type I (ADOI) caused by a T253I mutation in LRP5 are normal in vitro, but have decreased resorption capacity in vivo. Am J Pathol 167:1341–1348

    PubMed  CAS  Google Scholar 

  26. Sondergaard BC, Henriksen K, Wulf H et al (2006) Relative contribution of matrix metalloprotease and cysteine protease activities to cytokine-stimulated articular cartilage degradation. Osteoarthritis Cartilage 14:738–748

    Article  PubMed  CAS  Google Scholar 

  27. Henriksen K, Sorensen MG, Nielsen RH et al (2006) Degradation of the organic phase of bone by osteoclasts - a secondary role for lysosomal acidification. J Bone Miner Res 21:58–66

    Article  PubMed  CAS  Google Scholar 

  28. Malone JD, Teitelbaum SL, Griffin GL et al. (1982) Recruitment of osteoclast precursors by purified bone matrix constituents. J Cell Biol 92:227–230

    Article  PubMed  CAS  Google Scholar 

  29. Martini MC, Osdoby P, Caplan AI (1982) Adhesion of osteoclasts and monocytes to developing bone. J Exp Zool 224:345–354

    Article  PubMed  CAS  Google Scholar 

  30. Krukowski M, Kahn AJ (1982) Inductive specificity of mineralized bone matrix in ectopic osteoclast differentiation. Calcif Tissue Int 34:474–479

    Article  PubMed  CAS  Google Scholar 

  31. Hentunen TA, Cunningham NS, Vuolteenaho O et al (1994) Osteoclast recruiting activity in bone matrix. Bone Miner 25:183–198

    Article  PubMed  CAS  Google Scholar 

  32. Groessner-Schreiber B, Krukowski M, Hertweck D et al (1991) Osteoclast formation is related to bone matrix age. Calcif Tissue Int 48:335-340

    Article  PubMed  CAS  Google Scholar 

  33. Groessner-Schreiber B, Krukowski M, Lyons C et al (1992) Osteoclast recruitment in response to human bone matrix is age related. Mech Ageing Dev 62:143–154

    Article  PubMed  CAS  Google Scholar 

  34. Triffitt JT, Gebauer U, Ashton BA et al (1976) Origin of plasma alpha2HS-glycoprotein and its accumulation in bone. Nature 262:226–227

    Article  PubMed  CAS  Google Scholar 

  35. Melton LJ III, Khosla S, Atkinson EJ et al (1997) Relationship of bone turnover to bone density and fractures. J Bone Miner Res 12:1083–1091

    Article  PubMed  Google Scholar 

  36. Garnero P, Sornay-Rendu E Chapuy MC et al (1996) Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 11:337–349

    Article  PubMed  CAS  Google Scholar 

  37. Verborgt O, Gibson GJ, Schaffler MB (2000) Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J Bone Miner Res 15:60–67

    Article  PubMed  CAS  Google Scholar 

  38. Mullender MG, van der Meer DD, Huiskes R et al (1996) Osteocyte density changes in aging and osteoporosis. Bone 18:109–113

    Article  PubMed  CAS  Google Scholar 

  39. Schaffler MB, Choi K, Milgrom C (1995) Aging and matrix microdamage accumulation in human compact bone. Bone 17:521–525

    Article  PubMed  CAS  Google Scholar 

  40. Bronckers AL, Goei W, Luo G et al (1996) DNA fragmentation during bone formation in neonatal rodents assessed by transferase-mediated end labeling. J Bone Miner Res 11:1281–1291

    PubMed  CAS  Google Scholar 

  41. Mori S, Burr DB (1993) Increased intracortical remodeling following fatigue damage. Bone 14:103–109

    Article  PubMed  CAS  Google Scholar 

  42. Gazit D, Zilberman Y, Turgeman G et al (1999) Recombinant TGF-beta1 stimulates bone marrow osteoprogenitor cell activity and bone matrix synthesis in osteopenic, old male mice. J Cell Biochem 73:379–389

    Article  PubMed  CAS  Google Scholar 

  43. Hughes DE, Dai A, Tiffee JC et al (1996) Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 2:1132–1136

    Article  PubMed  CAS  Google Scholar 

  44. Ikeda T, Nagai Y, Yamaguchi A et al (1995) Age-related reduction in bone matrix protein mRNA expression in rat bone tissues: application of histomorphometry to in situ hybridization. Bone 16:17–23

    Article  PubMed  CAS  Google Scholar 

  45. Odetti P, Rossi S, Monacelli F et al (2005) Advanced glycation end products and bone loss during aging. Ann NY Acad Sci 1043:710–717; 2005

    Article  PubMed  CAS  Google Scholar 

  46. Cloos PA, Christgau S (2004) Post-translational modifications of proteins: implications for aging, antigen recognition, and autoimmunity. Biogerontology 5:139–158

    Article  PubMed  CAS  Google Scholar 

  47. Ishijima M, Rittling SR, Yamashita T et al (2001) Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin. J Exp Med 193:399–404

    Article  PubMed  CAS  Google Scholar 

  48. Miyata T, Notoya K, Yoshida K et al (1997) Advanced glycation end products enhance osteoclast-induced bone resorption in cultured mouse unfractionated bone cells and in rats implanted subcutaneously with devitalized bone particles. J Am Soc Nephrol 8:260–270

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmos Bioscience A/S & Nordic Bioscience A/S, Herlev, DK-2730, Denmark

    K. Henriksen, D. J. Leeming, I. Byrjalsen, R. H. Nielsen, M. G. Sorensen, P. Qvist & M. A. Karsdal

  2. HS Blodbank, The University Hospital of Copenhagen, Copenhagen, Denmark

    M. H. Dziegiel

  3. St. Vincent’s Institute of Medical Research, Melbourne, Australia

    T. John Martin

  4. Center for Clinical and Basic Research, CCBR, Ballerup, Denmark

    C. Christiansen

Authors
  1. K. Henriksen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. J. Leeming
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Byrjalsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. H. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. G. Sorensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. H. Dziegiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T. John Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. Christiansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P. Qvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M. A. Karsdal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. A. Karsdal.

Additional information

Kim Henriksen and Diana J. Leeming contributed equally.

Financial disclosure: Morten A. Karsdal, Per Qvist and Claus Christiansen own stock options in Nordic Bioscience A/S

Rights and permissions

Reprints and permissions

About this article

Cite this article

Henriksen, K., Leeming, D.J., Byrjalsen, I. et al. Osteoclasts prefer aged bone. Osteoporos Int 18, 751–759 (2007). https://doi.org/10.1007/s00198-006-0298-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-006-0298-4

Keywords

Search

Navigation