Table 3.

Summary of skeleton-derived factors acting on vasculature

Factors	Sources	Targets	Effects	Mechanisms	References
OCN	• Osteoblast	• Endothelial cell	• Protect vascular endothelial cell functions • Prevent atherosclerosis progression	• Upregulate NO and NF-кB signals • Stimulate PI3K/Akt/eNOS pathway	127,133,137
PDGF-BB	• Preosteoclast	• Endothelial progenitor cell • Mesenchymal stem cell	• Enhance capillary abundance • Stabilize tube formation • Mediate osteoblast differentiation	• Trigger PI3K/Akt signaling cascade	141,144,145
SLIT3	• Osteoblast	• Endothelial cell	• Promote tube formation and angiogenesis • Help bone remodeling and fracture repair	• Activate ERK mitogen-activated protein kinase and Hippo signaling pathway	150,151
VEGF	• Osteoblast • Chondrocyte	• Endothelial cell • Osteoprogenitor	• Promote angiogenesis process • Modulate bone development and homeostasis	• Induced by hypoxia via HIF-dependent pathway • Promote induction of β-catenin and activate Wnt signaling pathway	156–158,160
FGF	• Osteoblast • Chondrocyte	• Endothelial cell	• Promote angiogenesis process • Elevate vessel permeability	• Induce EC proliferation, chemotaxis, and intercellular gap-junction communication	165–167,170
MMP	• Osteoclast • Osteoblast • Chondrocyte	• Endothelial cell	• Contribute to vascular lumen formation	• Via ERK, AKT, or PI3K and SRC pathways • Release angiogenic factors (VEGF, etc.) from matrix	176–179,182
LCN-2	• Osteoblast • Adipocyte	• Endothelial cell	• Make for proper endothelial function • Involved in cardiovascular progression	• Potentiated via IL-1β mediated pathway	97,184,188,189

OCN osteocalcin, PDGF-BB platelet-derived growth factor-BB, SLIT3 slit homolog 3 protein, ERK extracellular signal regulated kinase, VEGF vascular endothelial growth factor, HIF hypoxia-inducible factor, FGF fibroblast growth factor, MMP matrix metalloprotease, LCN-2 lipocalin-2