Osteoblast Recruitment and Bone Formation Enhanced by Cell Matrix–associated Heparin-binding Growth-associated Molecule (HB-GAM)

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.

Increased trabecular bone formation in mice lacking the growth factor midkine

“…In fact, the three transgenic mouse models overexpressing Ptn all display a higher bone mineral density, which is in line with in vitro experiments demonstrating that Ptn promotes migration, differentiation, and function of osteoblasts. (21)(22)(23)(44)(45)(46) In addition, there is recent evidence that these effects are also of physiologic relevance because low bone formation and osteopenia have been described in mice lacking Ptn. (47) Given the fact that our own analysis of Ptn-deficient mice did not reveal such a phenotype compared with wild-type littermates on a mixed genetic background, it appears that the backcrossing of the Ptn deficiency into a 129S2/SV genetic background is primarily responsible for the discrepancies between the two publications.…”

“…In fact, there are three published transgenic mouse models overexpressing Ptn, all of them displaying a bone phenotype. (21)(22)(23) Together with the fact that Ptn was identified originally not only in the developing brain but also in cultured osteoblasts, and given the positive effect of Ptn on osteoblast proliferation and differentiation in vitro, we embarked previously on the skeletal analysis of a Ptn-deficient mouse model to address the question of whether Ptn is physiologically involved in the regulation of bone remodeling. (24)(25)(26)(27) Unexpectedly, however, our analysis did not reveal any defect of skeletal development and remodeling caused by the absence of Ptn.…”

Type XII collagen regulates osteoblast polarity and communication during bone formation

“…Bone formation begins with the differentiation of osteoblasts from pluripotent mesenchymal cells. The progenitors migrate to the sites of bone matrix deposition and differentiate into fully functional, bone matrix-producing osteoblasts (Imai et al, 1998). These events are regulated by the expression of runtrelated gene 2 (Runx2, also known as Cbfa1) and sp7 transcription factor (Sp7, also known as osterix) and by canonical Wnt signaling followed by the secretion of specific bone matrix proteins such as type I collagen (Col1a1), secreted phosphoprotein1 (Spp1, also known as osteopontin), integrin-binding sialoprotein (Ibsp), and bone -carboxyglutamate protein (Bglap, also known as osteocalcin; Harada and Rodan, 2003;Koga et al, 2005).…”

A New Flap Technique for Reconstruction of Microtia and Congenital Aural Atresia

“…The advantages of the new flap technique are as follows: (1) the three flaps are easy to design and easy to harvest in the operative field according to the anatomic variation of the patients; (2) the size of the PSTF flap and PP flap can be adjusted according to the canal to cover the exposed mastoid air cells and tympanic antrum, thus possibly avoiding postoperative stenosis and chronic drainage as far as possible; (3) the fascia flap and periosteal flap are relatively less deformed than the skin or other soft tissues, therefore reducing the possibility of canal stenosis; (4) the periosteum may induce new bone formation to its undersurface and some site-specific regulation, timely contouring the newly formed canal and inhibiting bony overgrowth [14,15]; (5) the PPS flap with saccate form can maintain the exact shape of the new canal with less inflammation and less flap displacement in the period of resurfacing; (6) Fig. 2 Postoperative photographs of different patients at different periods.…”