Endothelial Notch activity promotes angiogenesis and osteogenesis in bone
Open accessAbstract
Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralization, chondrocyte maturation, the formation of trabeculae and osteoprogenitor numbers in endothelial-cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.
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Type H vessels are surrounded by abundant osteoprogenitors and are located in the metaphysis and diaphysis.
“Type H vessels are surrounded by abundant osteoprogenitors (Osterix-positive cells) and are located both in the metaphysis, close to the growth plate, and in the diaphysis (periosteum and endosteum).128,129”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [129]
Type H vessels support perivascular osteoprogenitor differentiation by producing Noggin via Notch/Dll4 signaling and express CD31 and Endomucin at high levels.
“a specific capillary subtype that supports perivascular osteoprogenitor differentiation by producing Nogging via Notch/Dll 4 signaling has been termed type H vessel, which express both CD31 and Endomucin at high levels.”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [129]
Endothelial specification strongly contributes to bone microarchitectural structures such as cortical versus trabecular bone, and the process of endothelium specification and its mutual interaction with osteogenesis is Notch dependent.
“For bone, it has been demonstrated that endothelial specification strongly contributes to microarchitectural structures—for example, cortical versus trabecular bone. Moreover, there is again an important contribution of Notch signaling since the process of endothelium specification and its mutual interaction with osteogenesis is Notch dependent [146,147,148,149,150].”
From Interactions between Muscle and Bone—Where Physics Meets Biology (2020) · cites this paper as [149]
Endothelial cells are essential for tissue regeneration.
“Endothelial cells (EC) are essential for tissue regeneration.”
From Interactions between Muscle and Bone—Where Physics Meets Biology (2020) · cites this paper as [149]
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- Authors
- Ramasamy, S. K., Kusumbe, A. P., Wang, L., & Adams, R. H.
- Affiliations
- University of Münster (DE)
- Corresponding author
- Adams, Ralf H.
- Venue
- Nature
- Published
- 2014-03-12
- Volume
- 507
- Issue
- 7492
- Pages
- 376-380
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4943529
- OpenAlex
- W2087363756
- Cited by
- 1,071
- References
- 30
- Citations by year
- 2026: 114 · 2025: 108 · 2024: 115 · 2023: 118 · 2022: 100 · 2021: 125 · 2020: 90 · 2019: 74 · 2018: 58 · 2017: 55 · 2016: 54 · 2015: 36 · 2014: 23
- FWCI
- 22.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Notch signaling, angiogenesis, bone formation, bone vascularity, endothelial cells, noggin, bone morphogenetic proteins, osteoprogenitors, HIF-1α, bone regeneration, chondrocyte maturation, trabecular bone formation, DLL4, bone loss, fracture healing, longitudinal bone growth
- MeSH terms
- Noggin Protein, Animals, Animals, Newborn, Blood Vessels, Bone and Bones, Bone Development, Calcification, Physiologic, Carrier Proteins, Endothelium, Vascular, Female, Male, Mice, Inbred C57BL, Osteogenesis, Signal Transduction, Neovascularization, Physiologic, Chondrocytes, Cell Proliferation, Mice, Receptors, Notch
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