Bone has an enormous capacity for growth, regeneration, and remodeling. This capacity is largely due to induction of osteoblasts that are recruited to the site of bone formation. The recruitment of osteoblasts has not been fully elucidated, though the immediate environment of the cells is likely to play a role via cell– matrix interactions. We show here that heparin-binding growth-associated molecule (HB-GAM), an extracellular matrix–associated protein that enhances migratory responses in neurons, is prominently expressed in the cell matrices that act as target substrates for bone formation. Intriguingly, N-syndecan, which acts as a receptor for HB-GAM, is expressed by osteoblasts/osteoblast precursors, whose ultrastructural phenotypes suggest active cell motility. The hypothesis that HB-GAM/N-syndecan interaction mediates osteoblast recruitment, as inferred from developmental studies, was tested using osteoblast-type cells that express N-syndecan abundantly. These cells migrate rapidly to HB-GAM in a haptotactic transfilter assay and in a migration assay where HB-GAM patterns were created on culture wells. The mechanism of migration is similar to that previously described for the HB-GAM–induced migratory response of neurons. Our hypothesis that HB-GAM/N-syndecan interaction participates in regulation of osteoblast recruitment was tested using two different in vivo models: an adjuvant-induced arthritic model and a transgenic model. In the adjuvant-induced injury model, the expression of HB-GAM and of N-syndecan is strongly upregulated in the periosteum accompanying the regenerative response of bone. In the transgenic model, the HB-GAM expression is maintained in mesenchymal tissues with the highest expression in the periosteum. The HB-GAM transgenic mice develop a phenotype characterized by an increased bone thickness. HB-GAM may thus play an important role in bone formation, probably by mediating recruitment and attachment of osteoblasts/osteoblast precursors to the appropriate substrates for deposition of new bone.
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16 November 1998
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November 16 1998
Osteoblast Recruitment and Bone Formation Enhanced by Cell Matrix–associated Heparin-binding Growth-associated Molecule (HB-GAM)
Shinji Imai,
Shinji Imai
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
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Marko Kaksonen,
Marko Kaksonen
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
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Erkki Raulo,
Erkki Raulo
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
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Tarja Kinnunen,
Tarja Kinnunen
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
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Carole Fages,
Carole Fages
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
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Xiaojuan Meng,
Xiaojuan Meng
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
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Merja Lakso,
Merja Lakso
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
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Heikki Rauvala
Heikki Rauvala
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
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Shinji Imai
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
Marko Kaksonen
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
Erkki Raulo
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
Tarja Kinnunen
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
Carole Fages
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
Xiaojuan Meng
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
Merja Lakso
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
Heikki Rauvala
*Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; ‡Institute of Biotechnology and Department of Biosciences, Division of Biochemistry, §Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
The excellent technical assistance of Seija Lehto, Eeva-Liisa Saarikalle, and Erja Huttu is gratefully acknowledged.
Address all correspondence to Shinji Imai, M.D., Ph.D., Department of Anatomy, Shiga University of Medical Science, Setatsukinowa-cho, Otsu-shi, Shiga-ken, 520-2192, Japan. Tel.: 81-77-548-2136. Fax: 81-77-548-2139. E-mail: [email protected]
Received:
July 24 1998
Revision Received:
September 30 1998
Online ISSN: 1540-8140
Print ISSN: 0021-9525
1998
J Cell Biol (1998) 143 (4): 1113–1128.
Article history
Received:
July 24 1998
Revision Received:
September 30 1998
Citation
Shinji Imai, Marko Kaksonen, Erkki Raulo, Tarja Kinnunen, Carole Fages, Xiaojuan Meng, Merja Lakso, Heikki Rauvala; Osteoblast Recruitment and Bone Formation Enhanced by Cell Matrix–associated Heparin-binding Growth-associated Molecule (HB-GAM) . J Cell Biol 16 November 1998; 143 (4): 1113–1128. doi: https://doi.org/10.1083/jcb.143.4.1113
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