Table 4.

Summary of skeletal and systematic diseases associated with vasculature pathological alterations

Skeletal/Systematic diseases	Potential effects/mechanisms	References
Aging	• Reduction of type H EC quantity and osterix-positive osteoprogenitor abundance. • Accumulation of defective HSCs and alterations in bone marrow stroma.	8,206,207
Osteoporosis	• Estrogen decrease causes EC dysfunction, leads to alterations of bone perfusion and bone mass. • Secondary risk factors like glucocorticoid inhibits PDGF-BB, leads to blood flow reduction and osteogenesis impairment.	141,144,206
Osteoarthritis	• The preosteoclasts secrete an excessive amount of PDGF-BB, mediating the development of aberrant subchondral bone angiogenesis. • Vascular signal production prompts mTORC1 activation in eroding articular cartilage. • Elevated pro-angiogenic factors mediate inflammatory infiltration, structural damage and nociceptive transmission in OA.	143,216,218
Fracture Nonunion	• Abnormal vasculature reduces local bone nutrient sources, increases metabolite deposition and impedes fracture healing efficiency. • Vascular dysfunction exerts detrimental impacts on osteogenic differentiation process and disruption of osteoblast-osteoclast equilibrium. • Inflammatory cells secret and recruit negative regulators towards local injury sites.	223,225,227
Avascular Necrosis	• EC damage and grume formation cause blood flow interruption and osteocyte death, articular surface collapse. • Decreased EC abundance and pro-angiogenic factor expression lead to decreased migration ability and increased senescence tendency.	232–234
Heterotopic Ossification	• Mesenchymal progenitors function as the major niche in expressing VEGF-A for accelerating ectopic bone formation. • Activation of modulators (BMPs and chondrogenic transcription factors) and loss of mineralization inhibitors (pyrophosphate) lead to HO-vascular calcification.	236–239
Diabetes Mellitus	• Microangiopathy causes impaired vasoconstriction and blood flow. • Hyperglycemia diverts BMSCs to a metabolically stressed adipogenic pathway instead of osteogenesis. • AGEs leads to EC dysfunction, pro-angiogenic factor deficiency and a cross-linked imbalance of bone-vessel equilibrium.	242–244
Osseous Neoplasm/Metastasis	• Matrix-abundant vascular microenvironment within bone provides fertile soils for metastatic growth. • PDGF-B from vessels provides arteriolar niches for HSCs and DTCs long-term maintaining. • Blood flow decline within bone conduce to interactions between tumor cells and skeletal ECs, thus developing into macrometastasis.	252–254

EC endothelial cell, HSC hematopoietic stem cell, mTORC1 mechanistic target of rapamycin complex 1, OA osteoarthritis, AGEs advanced glycation end products, DTC disseminated tumor cell