Abstract
Bone regeneration is a complex process requiring highly orchestrated interactions between different cells and signals to form new mineralized tissue. Blood vessels serve as a structural template, around which bone development takes place, and also bring together the key elements for bone homeostasis into the osteogenic microenvironment, including minerals, growth factors and osteogenic progenitor cells. Vascular endothelial growth factor (VEGF) is the master regulator of vascular growth and it is required for effective coupling of angiogenesis and osteogenesis during both skeletal development and postnatal bone repair. Here, we will review the current state of knowledge on the molecular cross-talk between angiogenesis and osteogenesis. In particular, we will focus on the role of VEGF in coupling these two processes and how VEGF dose can control the outcome, addressing in particular: (1) the direct influence of VEGF on osteogenic differentiation of mesenchymal progenitors; (2) the angiocrine functions of endothelium to regulate osteoprogenitors; (3) the role of immune cells, e.g., myeloid cells and osteoclast precursors, recruited by VEGF to the osteogenic microenvironment. Finally, we will discuss emerging strategies, based on the current biological understanding, to ensure rapid vascularization and efficient bone formation in regenerative medicine.
Highlights
Bone regeneration entails a complex series of biological events, with the interplay of different cell types and the orchestration of several intracellular and extracellular signaling pathways
Vascular endothelial growth factor-A (VEGF) A is one of the most important regulators of angiogenesis and it is critical for both bone development and regeneration
VEGF can upregulate bone morphogenetic protein (BMP) expression in endothelial cells (Figure 1B), inducing osteogenic differentiation and matrix mineralization. Both inactivation and overexpression of Noggin, a secreted BMP antagonist, in osteoblasts led to reduced bone mass, indicating the importance of Noggin levels during bone formation (Ramasamy et al, 2014)
Summary
Bone regeneration entails a complex series of biological events, with the interplay of different cell types and the orchestration of several intracellular and extracellular signaling pathways. HSC and progenitors have been found in the proximity of small arterioles and specialized sinusoids (Kunisaki et al, 2013), where different cell types, including endothelial cells, perycites, stromal progenitors and sympathetic neuronal cells, contribute to the maintenance of HSC self-renewal [for a comprehensive recent review, see Morrison and Scadden (2014)]. In addition to these well-known functions, blood vessels have been recently ascribed a so-called angiocrine function, i.e., providing paracrine signals that coordinate growth, differentiation, and regeneration of different tissues, including bone, where they can promote osteogenesis (Ramasamy et al, 2016). Angiogenesis and vascular cells can affect biological processes in the bone/marrow organ at several different levels
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