Expression of Vascular Endothelial Growth Factors and Their Receptors during Osteoblast Differentiation

Abstract

Endochondral bone formation is regulated by systemically and locally acting growth factors. A role for vascular endothelial growth factor (VEGF) in this process has recently been proposed, because inactivation of VEGF inhibits endochondral bone formation via inhibition of angiogenesis. Despite the known effect of VEGF as specific endothelial growth factor, its effects on osteoblast differentiation have not been studied. We, therefore, examined the expression of VEGF-A, -B, -C, and -D and their receptors in a model of osteoblast differentiation using the mouse preosteoblast-like cell line KS483. Early in differentiation, KS483 cells express low levels VEGF-A, -B, and -D messenger RNA, whereas during mineralization, KS483 cells express high levels. In addition, expression of the VEGF receptors, VEGFR1, VEGFR2, and VEGF165R/neuropilin, coincided with expression of their ligands, being maximally expressed during mineralization. VEGF-A production during osteoblast differentiation was stimulated by insulin-like growth factor I that enhances osteoblast differentiation and was inhibited by PTH-related peptide that inhibits osteoblast differentiation. Furthermore, continuous treatment of KS483 cells with recombinant human VEGF-A stimulated nodule formation. Although treatment of KS483 cells with soluble FLT1, an agent that blocks binding of VEGF-A and -B to VEGFR1, did not inhibit nodule formation, this observation does not exclude involvement of VEGFR2 in the regulation of osteoblast differentiation. As it is known that VEGF-A, -C, and -D can act through activation of VEGFR2, other isoforms might compensate for VEGF-A loss. The expression pattern of VEGFs and their receptors shown here suggests that VEGFs play an important role in the regulation of bone remodeling by attracting endothelial cells and osteoclasts and by stimulating osteoblast differentiation.

Induced membranes secrete growth factors including vascular and osteoinductive factors and could stimulate bone regeneration

“…I Journd qf' Ortl7opardie Research 22 (2004) 73-79 is responsible for stimulation of angiogenesis and prolonged edema [6]. Moreover, VEGF plays an important role in the regulation of bone remodeling by attracting endothelial cells and osteoclasts and by stimulating osteoblast differentiation [3]. Our data (immunohistochemistry and quantitative analysis) confirmed that these membranes continuously secrete this angiogenic factor, which is able to stimulate bone cell differentiation.…”

Vasculogenic and Osteogenesis-Enhancing Potential of Human Umbilical Cord Blood Endothelial Colony-Forming Cells

“…In addition, VEGF detected in ECFC-CM may have contributed significantly to the observed phenomena. VEGF has been reported to induce ALP activity in osteoblasts [34] and enhance osteoblast differentiation [35]. Behr et al also demonstrated that VEGF-A promotes osteogenic and endothelial differentiation [36], thus playing a significant role in skeletal repair [37].Other bone-morphogenic factors such as FGFs, PDGF, oncostatin M, and endoglin have also been reported to induce osteoblast differentiation.…”

Osteogenic Gene Expression Correlates With Development of Heterotopic Ossification in War Wounds

“…The ability of BMPs to increase the levels of VEGFA mRNA in a concentration and time-dependent fashion has been shown [12,23,51]. Additional synergy between diffusible osteogenic morphogens and proangiogenic factors has been shown to enhance the rate of ectopic bone growth through modulation of angiogenesis, recruitment and induction of local progenitor cells, and enhancement of cell survival [28,42].…”