Vascular Invasion and Osteoblast Activity in Bone Formation
Vascular invasion is essential for delivering osteoblast precursors—not mature osteoblasts—into developing bone, where these precursors then differentiate and deposit bone matrix on mineralized cartilage remnants. 1
The Critical Role of Vascular Invasion
Osteoblast precursors migrate with invading blood vessels in a pericyte-like fashion. During endochondral bone formation, osterix-expressing osteoblast precursors labeled in the perichondrium before vascular invasion subsequently give rise to trabecular osteoblasts, osteocytes, and stromal cells inside the developing bone. 1 These immature precursors intimately associate with invading blood vessels throughout their translocation into the cartilaginous template. 1
In contrast, mature osteoblasts from the perichondrium do not exhibit perivascular localization and remain confined to the outer cortex of developing bones. 1 This distinction is crucial: the coupled vascular and osteogenic transformation depends specifically on immature osteoblast precursors, not mature osteoblasts. 1
Vascular Invasion Can Occur Independent of Osteoclastic Activity
Angiogenesis and vascular invasion of mineralized cartilage can proceed even in the complete absence of osteoclastic bone resorption. 2 Studies in bisphosphonate-treated mice and osteopetrotic mouse mutants (c-fos knockout and op/op mice) demonstrated that capillaries invaded calcified cartilage despite the absence of functional osteoclasts. 2 This finding challenges the traditional view that osteoclastic resorption must precede vascular invasion.
Growth Factors Orchestrating the Process
VEGF plays a dual role by promoting both angiogenesis and osteoblast differentiation. 3 During the matrix synthesis and maturation phase:
- VEGF promotes angiogenesis and exerts antiapoptotic effects on bone-forming cells 3
- VEGFs (A, C, and D) and their receptors (VEGFR1, VEGFR2, and neuropilin) are maximally expressed during mineralization phases of osteoblast differentiation 4
- Continuous VEGF-A treatment stimulates nodule formation in osteoblast cultures 4
BMPs recruit and differentiate mesenchymal progenitor cells into the osteoblast lineage. 3 BMPs 2-4 and BMP-7 stimulate mesenchymal progenitor cell migration and osteoblast differentiation, with rhBMP-2 FDA-approved since 2004 for orthopedic and oral surgery applications. 3
The Hematopoietic System's Contribution
Factors from the hematopoietic system support vascular invasion of cartilage, though less effectively without proper transcription factor support. 5 When Cbfa1-deficient cartilage was transplanted into normal mouse spleens, the cartilage matrix became mineralized and was invaded by vascular vessels and osteoclasts, though this process was severely retarded compared to wild-type controls. 5 This demonstrates that bone marrow-derived factors can promote vascular invasion independent of certain osteogenic transcription factors, but optimal efficiency requires their cooperation. 5
Clinical Implications for Bone Regeneration
Insufficient graft vascularization is a major cause of bone regeneration failure. 3 Several bone regenerative procedures cannot ensure successful bone regeneration in major defects primarily due to graft exposure, necrosis, insufficient graft vascularization, and post-operative infection. 3
Growth factor therapy aims to enhance vascularization and osteoblast recruitment simultaneously. The application of rhBMP-2 combined with carriers has shown advantages including decreased surgical time, lower morbidity, and faster healing periods by stimulating both angiogenesis (via induced VEGF expression) and osteoblast differentiation. 3
Common Pitfalls to Avoid
- Do not assume mature osteoblasts migrate into developing bone—only immature precursors exhibit this perivascular migration pattern 1
- Do not assume osteoclastic resorption is required for vascular invasion—angiogenesis can proceed independently 2
- Recognize that bisphosphonates show no apparent effect on angiogenesis in endochondral bone formation models, making them safe for use in growing skeleton disorders 2