The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone
Open accessAbstract
The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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 [128]
In the citing paper
“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 [128]
In the citing paper
“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 [148]
In the citing paper
“Endothelial cells (EC) are essential for tissue regeneration.”
From Interactions between Muscle and Bone—Where Physics Meets Biology (2020) · cites this paper as [148]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Nakashima, K., Zhou, X., Kunkel, G., Zhang, Z., Deng, J. M., Behringer, R. R., & de Crombrugghe, B. (2002) · Cell · doi:10.1016/s0092-8674(01)00622-5 · Cited by 3,608
A global double-fluorescent Cre reporter mouse
Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L., & Luo, L. (2007) · genesis · doi:10.1002/dvg.20335 · Cited by 3,491
Liao, J., Wei, Q., Zou, Y., Fan, J., Song, D., Cui, J., Zhang, W., Zhu, Y., Ma, C., Hu, X. Y., et al. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000471945 · Cited by 2,742
Regulation of angiogenesis by hypoxia: role of the HIF system
Pugh, C. W., & Ratcliffe, P. J. (2003) · Nature Medicine · doi:10.1038/nm0603-677 · Cited by 2,520
Endothelial and perivascular cells maintain haematopoietic stem cells
Ding, L., Saunders, T. L., Enikolopov, G., & Morrison, S. J. (2012) · Nature · doi:10.1038/nature10783 · Cited by 2,031
Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis
Wang, Y., Nakayama, M., Pitulescu, M. E., Schmidt, T., Bochenek, M. L., Sakakibara, A., Adams, S., Davy, A., Deutsch, U., Lüthi, U., et al. (2010) · Nature · doi:10.1038/nature09002 · Cited by 1,276
Self-citationEndothelial Notch activity promotes angiogenesis and osteogenesis in bone
Ramasamy, S. K., Kusumbe, A. P., Wang, L., & Adams, R. H. (2014) · Nature · doi:10.1038/nature13146 · Cited by 1,071
Self-citationMaes, C., Kobayashi, T., Selig, M. K., Torrekens, S., Roth, S. I., Mackem, S., Carmeliet, G., & Kronenberg, H. M. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.07.010 · Cited by 940
Tanimoto, K., Makino, Y., Pereira, T., & Poellinger, L. (2000) · The EMBO Journal · doi:10.1093/emboj/19.16.4298 · Cited by 928
Ullah, M. S., Davies, A. J., & Halestrap, A. P. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511397200 · Cited by 894
Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia
Parmar, K., Mauch, P., Vergilio, J.-A., Sackstein, R., & Down, J. D. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701152104 · Cited by 867
Yin, T. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28568 · Cited by 809
Fate tracing reveals the endothelial origin of hematopoietic stem cells
Zovein, A. C., Hofmann, J. J., Lynch, M., French, W. J., Turlo, K. A., Yang, Y., Becker, M. S., Zanetta, L., Dejana, E., Gasson, J. C., et al. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.09.018 · Cited by 691
Hooper, A. T., Butler, J. M., Nolan, D. J., Kranz, A., Iida, K., Kobayashi, M., Kopp, H., Shido, K., Petit, I., Yanger, K., et al. (2009) · Cell stem cell · doi:10.1016/j.stem.2009.01.006 · Cited by 662
Park, D., Spencer, J. A., Koh, B. I., Kobayashi, T., Fujisaki, J., Clemens, T. L., Lin, C. P., Kronenberg, H. M., & Scadden, D. T. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.02.003 · Cited by 637
THE NORMAL VASCULAR ANATOMY OF THE FEMORAL HEAD IN ADULT MAN
Trueta, J., & Harrison, M. H. M. (1953) · Journal of Bone and Joint Surgery - British Volume · doi:10.1302/0301-620x.35b3.442 · Cited by 592
The Bone Marrow Vascular Niche: Home of HSC Differentiation and Mobilization
Kopp, H., Avecilla, S. T., Hooper, A. T., & Rafii, S. (2005) · Physiology · doi:10.1152/physiol.00025.2005 · Cited by 581
Butler, J. M., Kobayashi, H., & Rafii, S. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2791 · Cited by 578
Tang, N., Wang, L., Esko, J. D., Giordano, F. J., Huang, Y., Gerber, H., Ferrara, N., & Johnson, R. S. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.09.026 · Cited by 549
Nombela‐Arrieta, C., Pivarnik, G., Winkel, B., Canty, K. J., Harley, B. A. C., Mahoney, J. E., Park, S., Lu, J., Protopopov, A. I., & Silberstein, L. E. (2013) · Nature Cell Biology · doi:10.1038/ncb2730 · Cited by 543
Shapiro, F. (2008) · European Cells and Materials · doi:10.22203/ecm.v015a05 · Cited by 530
Heterogeneity of Endothelial Cells
Garlanda, C., & Dejana, E. (1997) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.17.7.1193 · Cited by 494
Burkhardt, R., Kettner, G., Böhm, W., Schmidmeier, M., Schlag, R., Frisch, B., Mallmann, B., Eisenmenger, W., & Gilg, T. (1987) · Bone · doi:10.1016/8756-3282(87)90015-9 · Cited by 452
Arterial–Venous Specification During Development
Swift, M. R., & Weinstein, B. M. (2009) · Circulation Research · doi:10.1161/circresaha.108.188805 · Cited by 442
Vascular tumors in livers with targeted inactivation of the von Hippel–Lindau tumor suppressor
Haase, V. H., Glickman, J. N., Socolovsky, M., & Jaenisch, R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1583 · Cited by 430
Mean wall thickness of trabecular bone packets in the human iliac crest: Changes with age
Lips, P. T. A. M., Courpron, P., & Meunier, P. J. (1978) · Calcified Tissue International · doi:10.1007/bf02013227 · Cited by 414
Angiogenesis in Fracture Repair
Glowacki, J. (1998) · Clinical Orthopaedics and Related Research · doi:10.1097/00003086-199810001-00010 · Cited by 386
Losordo, D. W., & Isner, J. M. (2001) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.21.1.6 · Cited by 354
Neuropilin-2 mediates VEGF-C–induced lymphatic sprouting together with VEGFR3
Xu, Y., Yuan, L., Mak, J., Pardanaud, L., Caunt, M., Kasman, I. M., Larrivée, B., Toro, R. D., Suchting, S., Medvinsky, A., et al. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.200903137 · Cited by 339
Arteriogenesis The Development and Growth of Collateral Arteries
Helisch, A., & Schaper, W. K. A. (2003) · Microcirculation · doi:10.1038/sj.mn.7800173 · Cited by 312
THE VASCULAR CONTRIBUTION TO OSTEOGENESIS
Trueta, J., & Morgan, J. D. (1960) · Journal of Bone and Joint Surgery - British Volume · doi:10.1302/0301-620x.42b1.97 · Cited by 286
Bone and the hematopoietic niche: a tale of two stem cells
Bianco, P. (2011) · Blood · doi:10.1182/blood-2011-01-315069 · Cited by 259
The loss of bone mineral with aging and its relationship to risk of fracture.
Smith, D. M., Khairi, M. R. A., & Johnston, C. C. (1975) · Journal of Clinical Investigation · doi:10.1172/jci108095 · Cited by 229
Increased skeletal VEGF enhances β‐catenin activity and results in excessively ossified bones
Maes, C., Goossens, S., Bartunkova, S., Drogat, B., Coenegrachts, L., Stockmans, I., Moermans, K., Nyabi, O., Haigh, K., Naessens, M., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.361 · Cited by 216
Arteriogenesis The Development and Growth of Collateral Arteries
Helisch, A., & Schaper, W. K. A. (2003) · Microcirculation · doi:10.1080/mic.10.1.83.97 · Cited by 200
Osteogenesis and Bone-Marrow-Derived Cells
Long, M. W. (2001) · Blood Cells Molecules and Diseases · doi:10.1006/bcmd.2001.0431 · Cited by 168
Endothelial Cell Heterogeneity and Organ Specificity
Ribatti, D., Nico, B., Vacca, A., Roncali, L., & Dammacco, F. (2002) · Stem Cells and Development · doi:10.1089/152581602753448559 · Cited by 163
The relationship between bone, hemopoietic stem cells, and vasculature
Ellis, S. L., Grassinger, J., Jones, A. S., Borg, J., Camenisch, T. D., Haylock, D. N., Bertoncello, I., & Nilsson, S. K. (2011) · Blood · doi:10.1182/blood-2010-08-303800 · Cited by 159
Effect of age on vascularization during fracture repair
Lu, C., Hansen, E., Sapozhnikova, A., Hu, D. P., Miclau, T., & Marcucio, R. (2008) · Journal of Orthopaedic Research® · doi:10.1002/jor.20667 · Cited by 153
Endothelium-Microenvironment Interactions in the Developing Embryo and in the Adult
Red‐Horse, K., Crawford, Y., Shojaei, F., & Ferrara, N. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.01.013 · Cited by 135
Eshkar-Oren, I., Viukov, S. V., Salameh, S., Krief, S., Oh, C., Akiyama, H., Gerber, H., Ferrara, N., & Zelzer, E. (2009) · Development · doi:10.1242/dev.034199 · Cited by 114
The interplay of osteogenesis and hematopoiesis
Kuznetsov, S. A., Riminucci, M., Ziran, N. M., Tsutsui, T. W., Corsi, A., Calvi, L. M., Kronenberg, H. M., Schipani, E., Robey, P. G., & Bianco, P. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200408079 · Cited by 114
Trueta, J., & Buhr, A. J. (1963) · Journal of Bone and Joint Surgery - British Volume · doi:10.1302/0301-620x.45b3.572 · Cited by 97
Tashiro, Y., Nishida, C., Sato-Kusubata, K., Ohki, M., Ishihara, M., Sato, A., Gritli, I., Komiyama, H., Sato, Y., Dan, T., et al. (2012) · Blood · doi:10.1182/blood-2011-12-399659 · Cited by 82
Rodríguez, J., Calvo, F., González, J. M., Casar, B., Andrés, V., & Crespo, P. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201004067 · Cited by 82
Identification of a clonally expanding haematopoietic compartment in bone marrow
Wang, L., Benedito, R., Bixel, M. G., Zeuschner, D., Stehling, M., Savendahl, L. S., Haigh, J. J., Snippert, H. J. G., Clevers, H. C., Breier, G., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.308 · Cited by 81
Self-citationPATHOPHYSIOLOGY OF OSTEOPOROSIS
Heaney, R. P. (1998) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70004-9 · Cited by 81
Boado, R. J., & Pardridge, W. M. (2002) · Journal of Neurochemistry · doi:10.1046/j.0022-3042.2001.00756.x · Cited by 78
Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages
Šale, S., Lafkas, D., & Artavanis‐Tsakonas, S. (2013) · Nature Cell Biology · doi:10.1038/ncb2725 · Cited by 75
Jones, D. T., & Harris, A. L. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0443 · Cited by 68
A REVISION OF THE ANATOMY OF THE ARTERIES SUPPLYING THE UPPER END OF THE HUMAN FEMUR.
Hv, C. (1965) · PubMed · Cited by 62
Kataoka, M., & Tavassoli, M. (1985) · Blood · doi:10.1182/blood.v65.5.1163.1163 · Cited by 45
Skawina, A., Litwin, J. A., Gorczyca, J., & Miodoński, A. J. (1994) · PubMed · Cited by 39
Flagged first, then by citations
Cited by
Sorted by citations
Liao, J., Wei, Q., Zou, Y., Fan, J., Song, D., Cui, J., Zhang, W., Zhu, Y., Ma, C., Hu, X. Y., et al. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000471945 · Cited by 2,742
Mechanisms of bone development and repair
Salhotra, A., Shah, H. N., Lévi, B., & Longaker, M. T. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00279-w · Cited by 1,302
Endothelial Notch activity promotes angiogenesis and osteogenesis in bone
Ramasamy, S. K., Kusumbe, A. P., Wang, L., & Adams, R. H. (2014) · Nature · doi:10.1038/nature13146 · Cited by 1,071
Self-citationHaematopoietic stem cell activity and interactions with the niche
Pinho, S., & Frenette, P. S. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0103-9 · Cited by 1,064
PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis
Xie, H., Cui, Z., Wang, L., Xia, Z., Hu, Y., Xian, L., Li, C., Xie, L., Crane, J., Wan, M., et al. (2014) · Nature Medicine · doi:10.1038/nm.3668 · Cited by 951
Metadata
- Authors
- Kusumbe, A. P., Ramasamy, S. K., & Adams, R. H.
- Affiliations
- University of Münster (DE)
- Corresponding author
- Adams, Ralf H.
- Venue
- Nature
- Published
- 2014-03-12
- Volume
- 507
- Issue
- 7492
- Pages
- 323-328
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4943525
- OpenAlex
- W2089254126
- Cited by
- 2,155
- References
- 53
- Citations by year
- 2026: 247 · 2025: 231 · 2024: 270 · 2023: 223 · 2022: 222 · 2021: 238 · 2020: 203 · 2019: 136 · 2018: 114 · 2017: 93 · 2016: 76 · 2015: 63 · 2014: 36
- FWCI
- 36.60
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-09-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Max-Planck-Gesellschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- angiogenesis, bone formation, bone vascularity, endomucin, CD31, osteoprogenitors, HIF-1α, Notch signaling, bone aging, bone homeostasis, bone regeneration, fracture healing, bone loss
- MeSH terms
- Aging, Animals, Blood Vessels, Bone and Bones, Male, Mice, Inbred C57BL, Osteoblasts, Osteogenesis, Oxygen, Stem Cells, Neovascularization, Physiologic, Endothelial Cells, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review