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J. Cell Biol.,
Volume 143, Number 4, November 16, 1998 1113-1128
§§
* Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan; 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.
Institute of Biotechnology and
Department of Biosciences, Division of Biochemistry, § Transgenic Unit, University of Helsinki, Helsinki, FIN-00014, Finland
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