Osteoblast recruitment to sites of bone formation in skeletal development, homeostasis, and regeneration

Abstract

During endochondral bone development, bone-forming osteoblasts have to colonize the regions of cartilage that will be replaced by bone. In adulthood, bone remodeling and repair require osteogenic cells to reach the sites that need to be rebuilt, as a prerequisite for skeletal health. A failure of osteoblasts to reach the sites in need of bone formation may contribute to impaired fracture repair. Conversely, stimulation of osteogenic cell recruitment may be a promising osteo-anabolic strategy to improve bone formation in low bone mass disorders such as osteoporosis and in bone regeneration applications. Yet, still relatively little is known about the cellular and molecular mechanisms controlling osteogenic cell recruitment to sites of bone formation. In vitro, several secreted growth factors have been shown to induce osteogenic cell migration. Recent studies have started to shed light on the role of such chemotactic signals in the regulation of osteoblast recruitment during bone remodeling. Moreover, trafficking of osteogenic cells during endochondral bone development and repair was visualized in vivo by lineage tracing, revealing that the capacity of osteoblast lineage cells to move into new bone centers is largely confined to undifferentiated osteoprogenitors, and coupled to angiogenic invasion of the bone-modeling cartilage intermediate. It is well known that the presence of blood vessels is absolutely required for bone formation, and that a close spatial and temporal relationship exists between osteogenesis and angiogenesis. Studies using genetically modified mouse models have identified some of the molecular constituents of this osteogenic-angiogenic coupling. This article reviews the current knowledge on the process of osteoblast lineage cell recruitment to sites of active bone formation in skeletal development, remodeling, and repair, considering the role of chemo-attractants for osteogenic cells and the interplay between osteogenesis and angiogenesis in the control of bone formation.

Fucoidan Induces Cell Aggregation and Apoptosis in Osteosarcoma MG-63 Cells

“…These results suggested that fucoidan can be used in bone health supplements and as an additive for biomaterial-based scaffolds to promote bone regeneration. Efficient bone regeneration and repair is mediated by directed cell migration of osteoblasts to sites in need of bone formation (Pignolo & Kassem 2011;Dirckx et al 2013;Meng & Xie 2014;Song & Park 2014). Some controversial effects of fucoidan on cell migration have been reported in several types of cancer cells.…”

Fibroblast growth factor signaling in skeletal development and disease

“…In addition, FGF2 may also increase angiogenesis at the site of injury. A close spatial and temporal relationship exists between FGF signaling in skeletal development and disease GENES & DEVELOPMENTangiogenesis and osteogenesis during bone repair and endochondral bone formation, and the connection between the two processes is essential for bone formation (Dirckx et al 2013;Saran et al 2014). Recent genetic studies indicate that FGF/FGFR signaling plays an essential role in both processes.…”

Angiogenic–osteogenic coupling: the endothelial perspective

“…Altered levels of EC-derived VEGF secreted in the bone microenvironment (speculatively increased in the VHL and decreased in the HIF-1a iEC-cKO models) could also have contributed directly to the changes in ossification due to its paracrine stimulatory effects on osteoblast lineage cells. VEGF is known to regulate the migration, proliferation and differentiation of osteogenic cells (reviewed in Dirckx et al 10 ), and its temporary overexpression in postnatal long bones has previously been shown to result in a marked phenotype of aberrant angiogenesis and osteogenesis, bone marrow fibrosis and hematopoietic alterations. 13 It is important to recognize though that the VHL/HIF pathway regulates several other targets, including cellular metabolic pathways, which might have been altered in the mouse models studied here.…”

“…More recent evidence suggests that blood vessels may even have a role in determining the site of bone formation by carrying osteoprogenitors or mesenchymal stem cells with osteoblastic differentiation potential in close association with the endothelial wall of skeletal blood vessels (see Figure 1). [8][9][10] Conversely, the osteo-chondrocytic cellular compartments of the bones are known to determine the growth and integrity of the vascular bed. Studies using genetically altered mice and modulatory compounds have provided compelling evidence that the angiogenic growth factor VEGF is critical in driving angiogenesis in developing, growing and healing long bones.…”