Role of angiocrine signals in bone development, homeostasis and disease

Abstract

Skeletal vasculature plays a central role in the maintenance of microenvironments for osteogenesis and haematopoiesis. In addition to supplying oxygen and nutrients, vasculature provides a number of inductive factors termed as angiocrine signals. Blood vessels drive recruitment of osteoblast precursors and bone formation during development. Angiogenesis is indispensable for bone repair and regeneration. Dysregulation of the angiocrine crosstalk is a hallmark of ageing and pathobiological conditions in the skeletal system. The skeletal vascular bed is complex, heterogeneous and characterized by distinct capillary subtypes (type H and type L), which exhibit differential expression of angiocrine factors. Furthermore, distinct blood vessel subtypes with differential angiocrine profiles differentially regulate osteogenesis and haematopoiesis, and drive disease states in the skeletal system. This review provides an overview of the role of angiocrine signals in bone during homeostasis and disease.

Bone Vasculature and Bone Marrow Vascular Niches in Health and Disease

“…(4) However, the functionality of HSCs is not improved in these niche-activated aged mice, due to the cell-autonomous aspects of HSC aging, such as the accumulation of DNA damage. (7,99) Further, androgens via the androgen receptor in neurons can slow the agerelated cortical thinning in mice. (100) Age-associated decrease in HSC functionality in congruence with the changes in the cellular composition of the bone marrow is indicative of the critical role played by the microenvironment in regulating HSC aging.…”

Bone Angiogenesis and Vascular Niche Remodeling in Stress, Aging, and Diseases

“…Some of them are produced constitutively, while other factors modulate the production of angiocrine factors (Rafii et al, 2016). Angiocrine signals enable crosstalk between ECs and neighboring cell types, thereby contributing to various tissue functions, including maintenance of tissue homeostasis and regulation of stem cell behavior and differentiation (Ding et al, 2012;Sivan et al, 2019;Chen et al, 2020). BM ECs promote HSC maintenance and selfrenewal and blood vessel formation by expressing stimulating factors such as CXCL12, SCF, and vascular endothelial growth factor (VEGF) (Sugiyama et al, 2006;Coskun and Hirschi, 2010).…”

“…BM, bone marrow; HSC, hematopoietic stem cell, EC, endothelial cell; CSC, cancer stem cell; FGF, fibroblast-derived growth factor; TGF, transforming growth factor; CXCL12, C-X-C motif chemokine 12; VEGF, vascular endothelial growth factor; SLIT3, slit guidance ligand 3; BMP, bone morphogenetic protein; PDGF, platelet-derived growth factor; SCF, stem cell factor; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion protein; MMP, matrix metalloproteinase; HIF, hypoxia-inducible factor. proliferation and couple bone angiogenesis to bone remodeling (Tombran-Tink and Barnstable, 2004;Sivan et al, 2019; Figure 3). VEGFA has also been shown to be produced by HSCs (Gerber and Ferrara, 2003).…”

“…In the skeletal system, vasculature plays a crucial role in nutrient delivery and maintenance of the resident stem and progenitor cells that regulate osteogenesis and hematopoiesis. Bone marrow (BM) harbors stem and progenitor cells of different lineages including hematopoietic and mesenchymal stem cells that differentiate into a variety of mature functional cells, contributing to osteogenesis and hematopoiesis (Sivan et al, 2019). These stem and progenitor cells reside in specialized local microenvironments within the BM, known as BM niches (Colmone and Sipkins, 2008;Marenzana and Arnett, 2013).…”

Spatial Distribution of Macrophages During Callus Formation and Maturation Reveals Close Crosstalk Between Macrophages and Newly Forming Vessels

“…Bone development is initiated by blood vessel invasion, and the arrival of osteoprogenitors. Subsequently, specialized type H blood vessels secrete osteogenic factors, required for the induction of bone formation and growth (20). Although the presence of type H vessels has been reported at sites of bone regeneration (10,21), early events inducing the formation of these vessels in those situations have not yet been investigated.…”