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Osteoblast recruitment and bone formation enhanced by cell matrix-associated heparin-binding growth-associated molecule (HB-GAM).

Imai S, Kaksonen M, Raulo E, Kinnunen T, Fages C, Meng X, Lakso M, Rauvala H - J. Cell Biol. (1998)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan. simai@belle.shiga-med.ac.jp

ABSTRACT
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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Accelerated periosteal ossification after arthritic damage. (a) Normal  adult rat bone. The rectangle  corresponds to b and c. (b)  HB-GAM expression is  hardly seen in the healthy  adult bone. (The magnification for the rest of HB-GAM  immunostaining is the same.)  (c) No N-syndecan expression is observed in the  healthy adult bone. (The  magnification is the same for  the rest of N-syndecan immunostaining.) (d) Electron-microscopical localization of  HB-GAM in the osteocytic  lacunae (arrowheads) at day  7. oc, osteocyte. (e) An increase in the number of  HB-GAM–expressing osteocytes at day 7 (arrowhead).  (f) No expression of N-syndecan at day 7. (g) Electron-microscopical localization of  HB-GAM in the osteocytic  canaliculi (arrowheads) adjacent to the damaged bone  surface at day 10. (h) The  surface of the damaged bone  becomes immunoreactive to  HB-GAM (arrowhead) at  day 10. (i) N-syndecan is  noted for the first time at day  10 (arrowhead). (j) The periosteum is thickened at day 14. The rectangle corresponds to k and l. (k) The thickened periosteum is abundant in HB-GAM (asterisks) at day 14. (l) N-syndecan expression similar to the expression of HB-GAM (asterisks) at day 14. (m) The  thickened periosteum is mineralized at day 21. The rectangle corresponds to n and o. (n) HB-GAM expression disappears from the mineralized bone at day 21. (o) N-syndecan is downregulated at day 21. The rectangles in c, f, i, l, and o correspond to Fig. 5, a–e, respectively. cb, width of cortical bone; tp, width of thickened periosteum; mb, width of mineralized bone. Bars: (a, j, and m) 1,000 μm; (b and c)  100 μm; (d) 2.8 μm; (g) 4 μm.
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Figure 5: Accelerated periosteal ossification after arthritic damage. (a) Normal adult rat bone. The rectangle corresponds to b and c. (b) HB-GAM expression is hardly seen in the healthy adult bone. (The magnification for the rest of HB-GAM immunostaining is the same.) (c) No N-syndecan expression is observed in the healthy adult bone. (The magnification is the same for the rest of N-syndecan immunostaining.) (d) Electron-microscopical localization of HB-GAM in the osteocytic lacunae (arrowheads) at day 7. oc, osteocyte. (e) An increase in the number of HB-GAM–expressing osteocytes at day 7 (arrowhead). (f) No expression of N-syndecan at day 7. (g) Electron-microscopical localization of HB-GAM in the osteocytic canaliculi (arrowheads) adjacent to the damaged bone surface at day 10. (h) The surface of the damaged bone becomes immunoreactive to HB-GAM (arrowhead) at day 10. (i) N-syndecan is noted for the first time at day 10 (arrowhead). (j) The periosteum is thickened at day 14. The rectangle corresponds to k and l. (k) The thickened periosteum is abundant in HB-GAM (asterisks) at day 14. (l) N-syndecan expression similar to the expression of HB-GAM (asterisks) at day 14. (m) The thickened periosteum is mineralized at day 21. The rectangle corresponds to n and o. (n) HB-GAM expression disappears from the mineralized bone at day 21. (o) N-syndecan is downregulated at day 21. The rectangles in c, f, i, l, and o correspond to Fig. 5, a–e, respectively. cb, width of cortical bone; tp, width of thickened periosteum; mb, width of mineralized bone. Bars: (a, j, and m) 1,000 μm; (b and c) 100 μm; (d) 2.8 μm; (g) 4 μm.

Mentions: Normal adult rat bone hardly expresses HB-GAM (Fig. 5) or N-syndecan (Fig. 5 c, also see the rectangle in Fig. 5 a for orientation). To study possible participation of both molecules in regenerative ossification of adult bone, we used a postarthritic ossification model. Intracutaneous inoculation of Freund's adjuvant induces a systemic autoimmune-type arthritis ∼10 d after inoculation (day 10). After the arthritic damage, the periosteum goes through a direct intramembranous ossification (Fig. 5, j and m, rectangles) (Imai et al., 1997).


Osteoblast recruitment and bone formation enhanced by cell matrix-associated heparin-binding growth-associated molecule (HB-GAM).

Imai S, Kaksonen M, Raulo E, Kinnunen T, Fages C, Meng X, Lakso M, Rauvala H - J. Cell Biol. (1998)

Accelerated periosteal ossification after arthritic damage. (a) Normal  adult rat bone. The rectangle  corresponds to b and c. (b)  HB-GAM expression is  hardly seen in the healthy  adult bone. (The magnification for the rest of HB-GAM  immunostaining is the same.)  (c) No N-syndecan expression is observed in the  healthy adult bone. (The  magnification is the same for  the rest of N-syndecan immunostaining.) (d) Electron-microscopical localization of  HB-GAM in the osteocytic  lacunae (arrowheads) at day  7. oc, osteocyte. (e) An increase in the number of  HB-GAM–expressing osteocytes at day 7 (arrowhead).  (f) No expression of N-syndecan at day 7. (g) Electron-microscopical localization of  HB-GAM in the osteocytic  canaliculi (arrowheads) adjacent to the damaged bone  surface at day 10. (h) The  surface of the damaged bone  becomes immunoreactive to  HB-GAM (arrowhead) at  day 10. (i) N-syndecan is  noted for the first time at day  10 (arrowhead). (j) The periosteum is thickened at day 14. The rectangle corresponds to k and l. (k) The thickened periosteum is abundant in HB-GAM (asterisks) at day 14. (l) N-syndecan expression similar to the expression of HB-GAM (asterisks) at day 14. (m) The  thickened periosteum is mineralized at day 21. The rectangle corresponds to n and o. (n) HB-GAM expression disappears from the mineralized bone at day 21. (o) N-syndecan is downregulated at day 21. The rectangles in c, f, i, l, and o correspond to Fig. 5, a–e, respectively. cb, width of cortical bone; tp, width of thickened periosteum; mb, width of mineralized bone. Bars: (a, j, and m) 1,000 μm; (b and c)  100 μm; (d) 2.8 μm; (g) 4 μm.
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Figure 5: Accelerated periosteal ossification after arthritic damage. (a) Normal adult rat bone. The rectangle corresponds to b and c. (b) HB-GAM expression is hardly seen in the healthy adult bone. (The magnification for the rest of HB-GAM immunostaining is the same.) (c) No N-syndecan expression is observed in the healthy adult bone. (The magnification is the same for the rest of N-syndecan immunostaining.) (d) Electron-microscopical localization of HB-GAM in the osteocytic lacunae (arrowheads) at day 7. oc, osteocyte. (e) An increase in the number of HB-GAM–expressing osteocytes at day 7 (arrowhead). (f) No expression of N-syndecan at day 7. (g) Electron-microscopical localization of HB-GAM in the osteocytic canaliculi (arrowheads) adjacent to the damaged bone surface at day 10. (h) The surface of the damaged bone becomes immunoreactive to HB-GAM (arrowhead) at day 10. (i) N-syndecan is noted for the first time at day 10 (arrowhead). (j) The periosteum is thickened at day 14. The rectangle corresponds to k and l. (k) The thickened periosteum is abundant in HB-GAM (asterisks) at day 14. (l) N-syndecan expression similar to the expression of HB-GAM (asterisks) at day 14. (m) The thickened periosteum is mineralized at day 21. The rectangle corresponds to n and o. (n) HB-GAM expression disappears from the mineralized bone at day 21. (o) N-syndecan is downregulated at day 21. The rectangles in c, f, i, l, and o correspond to Fig. 5, a–e, respectively. cb, width of cortical bone; tp, width of thickened periosteum; mb, width of mineralized bone. Bars: (a, j, and m) 1,000 μm; (b and c) 100 μm; (d) 2.8 μm; (g) 4 μm.
Mentions: Normal adult rat bone hardly expresses HB-GAM (Fig. 5) or N-syndecan (Fig. 5 c, also see the rectangle in Fig. 5 a for orientation). To study possible participation of both molecules in regenerative ossification of adult bone, we used a postarthritic ossification model. Intracutaneous inoculation of Freund's adjuvant induces a systemic autoimmune-type arthritis ∼10 d after inoculation (day 10). After the arthritic damage, the periosteum goes through a direct intramembranous ossification (Fig. 5, j and m, rectangles) (Imai et al., 1997).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Shiga University of Medical Science, Shiga-ken, 520-2192, Japan. simai@belle.shiga-med.ac.jp

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus