OSTEOBLAST RECRUITMENT AND BONE-FORMATION ENHANCED BY CELL MATRIX-ASSOCIATED HEPARIN-BINDING GROWTH-ASSOCIATED MOLECULE (HB-GAM)

Bone has an enormous capacity for growth, regeneration, and remodeling . This capacity is largely due to induction of osteoblasts that are re cruited 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 extr acellular 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 motil ity. The hypothesis that HB-GAM/N-syndecan interaction mediates osteob last recruitment, as inferred from developmental studies, was tested u sing osteoblast-type cells that express N-syndecan abundantly. These c ells migrate rapidly to HB-GAM in a haptotactic transfilter assay and in a migration assay where HB-GAM patterns were created on culture wel ls. 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 osteo blast recruitment was tested using two different in vivo models: an ad juvant-induced arthritic model and a transgenic model. In the adjuvant -induced injury model, the expression of HB-GAM and of N-syndecan is s trongly upregulated in the periosteum accompanying the regenerative re sponse of bone. In the transgenic model, the HB-GAM expression is main tained in mesenchymal tissues with the highest expression in the perio steum. The HB-GAM transgenic mice develop a phenotype characterized by an increased bone thickness. HB-GAM may thus play an important role i n bone formation, probably by mediating recruitment and attachment of osteoblasts/osteoblast precursors to the appropriate substrates for de position of new bone.