Abstract
In vertebrates, new bone formation via intramembranous osteogenesis is a critical biological event for development, remodeling, and fracture healing of bones. Chemotaxis of osteoblast lineage cells is an essential cellular process in new bone formation. Connective tissue growth factor (CTGF) is known to exert chemotactic properties on various cells; however, details of CTGF function in the chemotaxis of osteoblast lineage cells and underlying molecular biological mechanisms have not been clarified. The aim of the present study was to evaluate the chemotactic properties of CTGF and its underlying mechanisms during active bone formation through intramembranous osteogenesis. In our mouse tensile force-induced bone formation model, preosteoblasts were aggregated at the osteogenic front of calvarial bones. CTGF was expressed at the osteogenic front, and functional inhibition of CTGF using a neutralizing antibody suppressed the aggregation of preosteoblasts. In vitro experiments using μ-slide chemotaxis chambers showed that a gradient of CTGF induced chemotaxis of preosteoblastic MC3T3-E1 cells, while a neutralizing integrin α5 antibody and a Ras inhibitor inhibited the CTGF-induced chemotaxis of MC3T3-E1 cells. These findings suggest that the CTGF-integrin α5-Ras axis is an essential molecular mechanism to promote chemotaxis of preosteoblasts during new bone formation through intramembranous osteogenesis.
Highlights
In vertebrates, new bone formation via intramembranous osteogenesis is a critical biological event for development, remodeling, and fracture healing of bones[1]
Tetracycline-labeled mineralized bone was clearly observed at the edges of the parietal bones at day 7 after tensile force loading, indicating active new bone formation induced by tensile force loading (Fig. 1c)
We hypothesized that Connective tissue growth factor (CTGF) is a novel chemoattractant to facilitate the chemotaxis of preosteoblasts at the sites of new bone formation during intramembranous osteogenesis
Summary
New bone formation via intramembranous osteogenesis is a critical biological event for development, remodeling, and fracture healing of bones[1]. Previous reports showed a close relation between mutations of Ras genes and craniosynostosis, a congenital malformation of cranial bones caused by premature fusion of cranial sutures[30,31] According to these notions, Ras is considered an important regulator of normal development and growth of bones. Ras is known to induce chemotaxis of mammalian cells, such as hematopoietic cells and smooth muscle cells[33,34] These findings suggest that Ras plays a key role in promoting chemotaxis, it is still unknown whether Ras exerts the chemotactic properties during development and growth of bones. The aim of the present study was to evaluate the chemotactic properties of CTGF and its underlying mechanisms during active bone formation through intramembranous osteogenesis. The underlying mechanisms of the CTGF-mediated chemotaxis of MC3T3-E1 cells were explored, focusing on integrin α5 and Ras
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