Skip to main content

Advertisement

SpringerLink
Log in

Polarization and secretion of cathepsin K precede tartrate-resistant acid phosphatase secretion to the ruffled border area during the activation of matrix-resorbing clasts

  • ORIGINAL ARTICLE
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

The activation sequence of clasts (the designation clast was used because ultrastructurally in this tissue, it is not always possible to differentiate between chondroclasts sitting on cartilage and osteoclasts sitting on bone matrix) was studied in vivo using the healing of low-phosphate, vitamin D-deficiency rickets as a model system. Thus, the bones of 7-week-old rachitic animals were analyzed with a combination of morphological, biochemical, and molecular biological methods at 48 and 72 h, respectively, after change to normal food. A quantitative ultrastructural analysis showed that the number of clast profiles exhibiting the characteristic polarized features of actively resorbing cells, i.e., ruffled borders and clear zones, had reached normal levels after 48 h. By combining the data with quantitative analyses by the immunogold technique, we demonstrated that cathepsin K secretion was coupled to ruffled border formation in clasts irrespective of whether the number of polarized clasts was low (in rickets) or high (in healing). In contrast, the levels of tartrate-resistant acid phosphatase (TRAP) both between ruffles and in the outside matrix adjoining the ruffled border were low in polarized clasts both in rickets and at the early (48 h) healing time-point, but were increased at the latest (72 h) healing time-point. Interestingly, expression of TRAP and the cathepsin K at the mRNA level, as well as protein expression and the activity of TRAP, were not different during the healing sequence. Although the two enzymes are confined to the same clast populations, their secretion during the resorption process is apparently differentially regulated: cathepsin K secretion is coupled to ruffled border formation in clasts, whereas TRAP is secreted at a later stage during the resorption sequence, suggesting a role for secreted TRAP as a modulator of resorptive activity.

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

Similar content being viewed by others

References

  1. M Mulari J Vääreniemi HK Väänänen (2003) ArticleTitleIntracellular membrane trafficking in bone resorbing osteoclasts Microsc Res Tech 61 496–503 Occurrence Handle10.1002/jemt.10371 Occurrence Handle12879417

    Article  PubMed  Google Scholar 

  2. WJ Boyle W Scott Simonet DL Lacey (2003) ArticleTitleOsteoclast differentiation and activation Nature 423 337–342 Occurrence Handle10.1038/nature01658 Occurrence Handle12748652

    Article  PubMed  Google Scholar 

  3. S Teitelbaum FP Ross (2003) ArticleTitleGenetic regulation of osteoclast development and function Nature Rev Genet 4 638–649 Occurrence Handle10.1038/nrg1122

    Article  Google Scholar 

  4. G Andersson A Lindunger B Ek-Rylander (1989) ArticleTitleIsolation and characterization of skeletal acid ATPase – a new osteoclast marker? Conn Tissue Res 20 151–158

    Google Scholar 

  5. C Minkin (1982) ArticleTitleBone acid phosphatase: tartrate-resistant acid phosphatase as a marker for osteoclast function Calcif Tissue Int 34 285–290 Occurrence Handle6809291

    PubMed  Google Scholar 

  6. J Nordahl G Andersson FP Reinholt (1998) ArticleTitleChondroclasts and osteoclasts in bones of young rats: comparison of ultrastructural and functional features Calcif Tissue Int 63 401–408 Occurrence Handle10.1007/s002239900548 Occurrence Handle9799825

    Article  PubMed  Google Scholar 

  7. AR Hayman SJ Jones A Boyde D Foster WK Colledge MB Carlton MJ Evans TM Cox (1996) ArticleTitleMice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis Development 122 3151–3162 Occurrence Handle8898228

    PubMed  Google Scholar 

  8. K Hollberg K Hultenby A Hayman T Cox G Andersson (2002) ArticleTitleOsteoclasts from mice deficient in tartrate-resistant acid phosphatase have altered ruffled borders and disturbed intracellular vesicular transport Exp Cell Res 279 227–238 Occurrence Handle10.1006/excr.2002.5612 Occurrence Handle12243748

    Article  PubMed  Google Scholar 

  9. NZ Angel N Walsh MR Forwood MC Ostrowski AI Cassady DA Hume (2000) ArticleTitleTransgenic mice overexpressing tartrate-resistant acid phosphatase exhibit an increased rate of bone turnover J Bone Miner Res 15 103–110 Occurrence Handle10646119

    PubMed  Google Scholar 

  10. B Ek-Rylander M Flores M Wendel D Heinegård G Andersson (1994) ArticleTitleDephosphorylation of osteopontin and bone sialoprotein by osteoclastic tartrate-resistant acid phosphatase J Biol Chem 269 14853–14856 Occurrence Handle8195113

    PubMed  Google Scholar 

  11. FP Reinholt K Hultenby A Oldberg D Heinegård (1990) ArticleTitleOsteopontin – a possible anchor of osteoclasts to bone Proc Natl Acad Sci USA 87 4473–4475 Occurrence Handle1693772

    PubMed  Google Scholar 

  12. ME Flores M Norgård D Heinegård FP Reinholt G Andersson (1992) ArticleTitleRGD-directed attachment of isolated rat osteoclasts to osteopontin, bone sialoprotein, and fibronectin Exp Cell Res 201 526–530 Occurrence Handle10.1016/0014-4827(92)90305-R Occurrence Handle1639145

    Article  PubMed  Google Scholar 

  13. S Razzouk JC Brunn C Qin CE Tye H Goldberg WT Butler (2002) ArticleTitleOsteopontin posttranslational modifications, possibly phosphorylation, are required for in vitro bone resorption but not osteoclast adhesion Bone 30 40–47 Occurrence Handle10.1016/S8756-3282(01)00637-8 Occurrence Handle11792563

    Article  PubMed  Google Scholar 

  14. FP Reinholt S Mengarelli-Widholm B Ek-Rylander G Andersson (1990) ArticleTitleUltrastructural localization of a tartrate-resistant ATPase in bone J Bone Min Res 5 1055–1061

    Google Scholar 

  15. A Suter V Everts A Boyde SJ Jones R Lullmann-Rauch D Hartmann A Hayman TM Cox MJ Evans T Meister K vonFigura P Saftig (2001) ArticleTitleOverlapping functions of lysosomal LAP and tartrate-resistant Acp5 revealed by doubly deficient mice Development 128 4899–4910 Occurrence Handle11731469

    PubMed  Google Scholar 

  16. JM Halleen S Räisänen JJ Salo SV Reddy GD Roodman TA Hentunen PP Lehenkari H Kaija P Vihko HK Väänänen (1999) ArticleTitleIntracellular fragmentation of bone resorption products by reactive oxygen species generated by osteoclastic tartrate-resistant acid phosphatase J Biol Chem 274 22907–22910 Occurrence Handle10.1074/jbc.274.33.22907 Occurrence Handle10438453

    Article  PubMed  Google Scholar 

  17. JM Halleen SR Räisanen SL Alatalo HK Väänänen (2003) ArticleTitlePotential function for the ROS-generating activity of TRACP J Bone Miner Res 18 1908–1911 Occurrence Handle14584905

    PubMed  Google Scholar 

  18. J Nordahl K Hollberg S Mengarelli-Widholm G Andersson FP Reinholt (2000) ArticleTitleMorphological and functional features of clasts in low-phosphate, vitamin D-deficiency rickets Calcified Tissue Int 67 400–407 Occurrence Handle10.1007/s002230001151

    Article  Google Scholar 

  19. M Gowen F Lazner R Dodds R Kapadia J Feild M Tavaria I Bertoncello F Drake S Zavarselk I Tellis P Hertzog C Debouck I Kola (1999) ArticleTitleCathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization J Bone Miner Res 14 1654–1663 Occurrence Handle10491212

    PubMed  Google Scholar 

  20. P Saftig E Hunziker O Wehmeyer S Jones A Boyde W Rommerskirch JD Moritz P Schu K von Figura (1998) ArticleTitleImpaired osteoclastic bone resorption leads to osteopetrosis in cathepsin K-deficient mice Proc Natl Acad Sci USA 95 13453–13458 Occurrence Handle10.1073/pnas.95.23.13453 Occurrence Handle9811821

    Article  PubMed  Google Scholar 

  21. T Kamiya Y Kobayashi K Kanaoka T Nakashima Y Kato A Mizuno H Sakai (1998) ArticleTitleFluorescence microscopic demonstration of cathepsin K activity as the major lysosomal cysteine proteinase in osteoclasts J Biochem 123 752–759 Occurrence Handle9538271

    PubMed  Google Scholar 

  22. B Ek-Rylander T Barkhem J Ljusberg L Ohman KK Andersson G Andersson (1997) ArticleTitleComparative studies of rat recombinant purple acid phosphatase and bone tartrate-resistant acid phosphatase Biochem J 321 305–311 Occurrence Handle9020859

    PubMed  Google Scholar 

  23. K Hultenby FP Reinholt A Oldberg D Heinegard (1991) ArticleTitleUltrastructural immunolocalization of osteopontin in metaphyseal and cortical bone Matrix 11 206–213 Occurrence Handle1870452

    PubMed  Google Scholar 

  24. FP Reinholt K Hultenby D Heinegård SC Marks SuffixJr M Norgård G Andersson (1999) ArticleTitleExtensive clear zone and defective ruffled border formation in osteoclasts of osteopetrotic (ia/ia) rats: implications for secretory function Exp Cell Res 251 477–491 Occurrence Handle10.1006/excr.1999.4585 Occurrence Handle10471332

    Article  PubMed  Google Scholar 

  25. M Norgård SC Marks SuffixJr FP Reinholt G Andersson (2003) ArticleTitleThe effects of colony stimulating factor (CSF-1) on the development of osteoclasts and their expression of tartrate-resistant acid phosphatase (TRAP) in toothless (tl-osteopetrotic) rats Crit Rev Eucaryotic Gene Expr 13 117–132 Occurrence Handle10.1615/CritRevEukaryotGeneExpr.v13.i24.50

    Article  Google Scholar 

  26. J Vääräniemi JM Halleen K Kaarlonen H Ylipahkala SL Alatalo G Andersson H Kaija P Vihko HK Väänänen (2004) ArticleTitleIntracellular machinery for matrix degradation in bone-resorbing osteoclasts J Bone Miner Res 19 1432–1440 Occurrence Handle15312243

    PubMed  Google Scholar 

  27. SA Nesbitt MA Horton (1997) ArticleTitleTrafficking of matrix collagens through bone-resorbing osteoclasts Science 276 266–269 Occurrence Handle10.1126/science.276.5310.266 Occurrence Handle9092478

    Article  PubMed  Google Scholar 

  28. J Salo P Lehenkari M Mulari K Metsikko HK Väänänen (1997) ArticleTitleRemoval of osteoclast bone resorption products by transcytosis Science 276 270–273 Occurrence Handle10.1126/science.276.5310.270 Occurrence Handle9092479

    Article  PubMed  Google Scholar 

  29. MTK Mulari H Zhao PT Lakkakorpi HK Väänänen (2003) ArticleTitleOsteoclast ruffled border has distinct subdomains for secretion and degraded matrix uptake Traffic 4 113–125 Occurrence Handle10.1034/j.1600-0854.2003.40206.x Occurrence Handle12559037

    Article  PubMed  Google Scholar 

  30. G Stenbeck MA Horton (2004) ArticleTitleEndocytic trafficking in actively resorbing osteoclasts J Cell Sci 117 827–836 Occurrence Handle10.1242/jcs.00935 Occurrence Handle14762112

    Article  PubMed  Google Scholar 

  31. G Andersson B Ek-Rylander K Hollberg J Ljusberg-Själander P Lång M Norgård Y Wang S-J Zhang (2003) ArticleTitleTRACP as an osteopontin phosphatase J Bone Mineral Res 18 1912–1915

    Google Scholar 

  32. J Ljusberg B Ek-Rylander G Andersson (1999) ArticleTitleTartrate-resistant purple acid phosphatase is synthesized as a latent proenzyme and activated by cysteine proteinases Biochem J 343 63–67 Occurrence Handle10.1042/0264-6021:3430063 Occurrence Handle10493912

    Article  PubMed  Google Scholar 

  33. J Ljusberg RA Dodds MW Lark M Gowen F Lazner I Kola G Andersson (1999) ArticleTitleTartrate-resistant acid phosphatase is proteolytically cleaved in vivo by cathepsin K J Bone Min Res 14 S358

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden

    Karin Hollberg, Joakim Nordahl, Silwa Mengarelli-Widholm & Göran Andersson

  2. Clinical Research Center, Karolinska University Hospital, Huddinge, Sweden

    Kjell Hultenby

  3. Institute and Department of Pathology, University of Oslo and Rikshospitalet University Hospital, NO-0027, Oslo, Norway

    Finn P. Reinholt

Authors
  1. Karin Hollberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joakim Nordahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kjell Hultenby
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silwa Mengarelli-Widholm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Göran Andersson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Finn P. Reinholt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Finn P. Reinholt.

About this article

Cite this article

Hollberg, K., Nordahl, J., Hultenby, K. et al. Polarization and secretion of cathepsin K precede tartrate-resistant acid phosphatase secretion to the ruffled border area during the activation of matrix-resorbing clasts. J Bone Miner Metab 23, 441–449 (2005). https://doi.org/10.1007/s00774-005-0626-3

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-005-0626-3

Key words

Search

Navigation