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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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Expression of HB-GAM during postnatal development  of bone. (a) HB-GAM is intensely expressed in the secondary ossification center, in the growth plate, and in the periosteum (i.e.,  perichondrium at this stage). (HB-GAM immunostaining, 1-wk-old rat, humeral head.) (b) Bone of the early postnatal life consists of woven bone that is formed during prenatal life and the  lamellar bone that has replaced the woven bone. The rectangle is  magnified in d (HB-GAM immunostaining, 3-wk-old rat, calcaneal bone). (c) Heidenhain's AZAN staining (Gabe, 1976) of the  cortical bone of the same specimen to distinguish the woven bone  (wb) from the lamellar bone (lb). (d) The osteocytes of the lamellar bone selectively express HB-GAM, whereas those of the woven bone do not. (e) HB-GAM is localized in the matrix surrounding the osteocytes (double arrows), in the canaliculi of the  osteocytes (arrow), and on the bone surface (arrowhead). Bars:  (b) 500 μm; (e) 60 μm.
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Figure 2: Expression of HB-GAM during postnatal development of bone. (a) HB-GAM is intensely expressed in the secondary ossification center, in the growth plate, and in the periosteum (i.e., perichondrium at this stage). (HB-GAM immunostaining, 1-wk-old rat, humeral head.) (b) Bone of the early postnatal life consists of woven bone that is formed during prenatal life and the lamellar bone that has replaced the woven bone. The rectangle is magnified in d (HB-GAM immunostaining, 3-wk-old rat, calcaneal bone). (c) Heidenhain's AZAN staining (Gabe, 1976) of the cortical bone of the same specimen to distinguish the woven bone (wb) from the lamellar bone (lb). (d) The osteocytes of the lamellar bone selectively express HB-GAM, whereas those of the woven bone do not. (e) HB-GAM is localized in the matrix surrounding the osteocytes (double arrows), in the canaliculi of the osteocytes (arrow), and on the bone surface (arrowhead). Bars: (b) 500 μm; (e) 60 μm.

Mentions: The postnatal growth of bone involves numerous anatomical sites of new bone formation. The metaphyseal part of the cartilage template remains as the growth plate that is responsible for the postnatal elongation of long bone. HB-GAM was abundantly expressed in the growth plate (Fig. 2 a), which remains throughout life in rodents. The physeal part of the cartilage gives rise to two types of cartilage, i.e., the outer portion of the cartilage becomes articular cartilage, and the inner portion of the cartilage provides a substrate for osteoblast recruitment by forming a secondary ossification center. HB-GAM was intensely expressed in the cartilage matrix that forms the hollow for the secondary ossification center, with the chondrocytes being presumptive cellular source of HB-GAM. In contrast, HB-GAM was not expressed in the outer portion that becomes the articular cartilage in future (Fig. 2 a).


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)

Expression of HB-GAM during postnatal development  of bone. (a) HB-GAM is intensely expressed in the secondary ossification center, in the growth plate, and in the periosteum (i.e.,  perichondrium at this stage). (HB-GAM immunostaining, 1-wk-old rat, humeral head.) (b) Bone of the early postnatal life consists of woven bone that is formed during prenatal life and the  lamellar bone that has replaced the woven bone. The rectangle is  magnified in d (HB-GAM immunostaining, 3-wk-old rat, calcaneal bone). (c) Heidenhain's AZAN staining (Gabe, 1976) of the  cortical bone of the same specimen to distinguish the woven bone  (wb) from the lamellar bone (lb). (d) The osteocytes of the lamellar bone selectively express HB-GAM, whereas those of the woven bone do not. (e) HB-GAM is localized in the matrix surrounding the osteocytes (double arrows), in the canaliculi of the  osteocytes (arrow), and on the bone surface (arrowhead). Bars:  (b) 500 μm; (e) 60 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2132954&req=5

Figure 2: Expression of HB-GAM during postnatal development of bone. (a) HB-GAM is intensely expressed in the secondary ossification center, in the growth plate, and in the periosteum (i.e., perichondrium at this stage). (HB-GAM immunostaining, 1-wk-old rat, humeral head.) (b) Bone of the early postnatal life consists of woven bone that is formed during prenatal life and the lamellar bone that has replaced the woven bone. The rectangle is magnified in d (HB-GAM immunostaining, 3-wk-old rat, calcaneal bone). (c) Heidenhain's AZAN staining (Gabe, 1976) of the cortical bone of the same specimen to distinguish the woven bone (wb) from the lamellar bone (lb). (d) The osteocytes of the lamellar bone selectively express HB-GAM, whereas those of the woven bone do not. (e) HB-GAM is localized in the matrix surrounding the osteocytes (double arrows), in the canaliculi of the osteocytes (arrow), and on the bone surface (arrowhead). Bars: (b) 500 μm; (e) 60 μm.
Mentions: The postnatal growth of bone involves numerous anatomical sites of new bone formation. The metaphyseal part of the cartilage template remains as the growth plate that is responsible for the postnatal elongation of long bone. HB-GAM was abundantly expressed in the growth plate (Fig. 2 a), which remains throughout life in rodents. The physeal part of the cartilage gives rise to two types of cartilage, i.e., the outer portion of the cartilage becomes articular cartilage, and the inner portion of the cartilage provides a substrate for osteoblast recruitment by forming a secondary ossification center. HB-GAM was intensely expressed in the cartilage matrix that forms the hollow for the secondary ossification center, with the chondrocytes being presumptive cellular source of HB-GAM. In contrast, HB-GAM was not expressed in the outer portion that becomes the articular cartilage in future (Fig. 2 a).

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