PlexinA2 mediates osteoblast differentiation via regulation of Runx2
Abstract
The imbalance between bone-resorbing osteoclasts and bone-forming osteoblasts often leads to bone destructive diseases such as osteoporosis. In contrast to the development of several antiresorptive agents for osteoporosis therapy, discovery of anabolic drugs has been difficult because of an insufficient understanding of the complex mechanism of bone formation. In a microarray analysis with mouse preosteoblast cells, we found that PlexinA2 (PlxnA2), a molecule previously known to mediate axon guidance in neural development, was upregulated by the osteogenic factor BMP2. PlxnA2-specific siRNA decreased Runx2 expression, osteoblast differentiation, and mineralization. Runx2 overexpression restored osteoblastic differentiation of PlxnA2-knockdown cells. PlxnA2 was associated with both type 1 and 2 BMP receptors, and BMP2 increased the interaction between PlxnA2 and type 1 receptors. PlxnA2 also affected Smad and Akt signaling pathways downstream of BMP2. Taken together, the results of our study reveal that PlxnA2 has a pro-osteogenic function by modulating BMP2 signaling. Therefore, PlxnA2 may be a useful target for development of bone anabolic therapeutics. © 2012 American Society for Bone and Mineral Research
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Genes with HHMCs such as PLXNA2, EVC2, MEPE, OMD, and SPAG17 are known to affect craniofacial bone and tooth morphologies.
“genes with HHMCs such as PLXNA2139, EVC2140, MEPE141, OMD142, and SPAG17143 are known to affect craniofacial bone and tooth morphologies.”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [139]
Cites
Osf2/Cbfa1: A Transcriptional Activator of Osteoblast Differentiation
Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L., & Karsenty, G. (1997) · Cell · doi:10.1016/s0092-8674(00)80257-3 · Cited by 4,246 · see citing works
Non-Smad pathways in TGF-β signaling
Zhang, Y. E. (2008) · Cell Research · doi:10.1038/cr.2008.328 · Cited by 1,754 · see citing works
Peng, X.-D., Xu, P.-Z., Chen, M.-L., Hahn-Windgassen, A., Skeen, J. E., Jacobs, J., Sundararajan, D., Chen, W. S., Crawford, S., Coleman, K., et al. (2003) · Genes & Development · doi:10.1101/gad.1089403 · Cited by 889 · see citing works
BMP receptor signaling: Transcriptional targets, regulation of signals, and signaling cross-talk
Miyazono, K., Maeda, S., & Imamura, T. (2005) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2005.01.009 · Cited by 888 · see citing works
Regulation of bone development and extracellular matrix protein genes by RUNX2
Komori, T. (2009) · Cell and Tissue Research · doi:10.1007/s00441-009-0832-8 · Cited by 806 · see citing works
A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic developmentPreprint
Ducy, P. F., Starbuck, M., Priemel, M., Shen, J., Pinero, G. J., Geoffroy, V., Amling, M., & Karsenty, G. (1999) · Genes & Development · doi:10.1101/gad.13.8.1025 · Cited by 772 · see citing works
Genetic Control of Bone Formation
Karsenty, G., Kronenberg, H. M., & Settembre, C. (2009) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.042308.113308 · Cited by 667 · see citing works
Wang, D., Christensen, K., Chawla, K., Xiao, G., Krebsbach, P. H., & Franceschi, R. T. (1999) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.1999.14.6.893 · Cited by 666 · see citing works
Semaphorin III is needed for normal patterning and growth of nerves, bones and heart
Behar, O., Golden, J. A., Mashimo, H. L., Schöen, F. J., & Fishman, M. C. (1996) · Nature · doi:10.1038/383525a0 · Cited by 583 · see citing works
Semaphorins command cells to move
Kruger, R. P., Aurandt, J., & Guan, K. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1740 · Cited by 496 · see citing works
Networks and hubs for the transcriptional control of osteoblastogenesis
Lian, J. B., Stein, G. S., Javed, A., van Wijnen, A. J., Stein, J. L., Montecino, M. A., Hassan, M. Q., Gaur, T., Lengner, C. J., & Young, D. W. (2006) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-006-9001-5 · Cited by 469 · see citing works
Fujita, T., Azuma, Y., Fukuyama, R., Hattori, Y., Yoshida, C. A., Koida, M., Ogita, K., & Komori, T. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200401138 · Cited by 462 · see citing works
Hanafusa, H., Ninomiya‐Tsuji, J., Masuyama, N., Nishita, M., Fujisawa, J., Shibuyà, H., Matsumoto, K., & Nishida, E. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.38.27161 · Cited by 442 · see citing works
Lee, M., Kim, Y. J., Kim, H., Park, H.-D., Kang, A. H., Kyung, H., Sung, J.-H., Wozney, J. M., Kim, H., & Ryoo, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211386200 · Cited by 409 · see citing works
Self-citationSignalling by semaphorin receptors: cell guidance and beyond
Tamagnone, L., & Comoglio, P. M. (2000) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)01816-x · Cited by 354 · see citing works
Lee, K., Hong, S.-H., & Bae, S. (2002) · Oncogene · doi:10.1038/sj.onc.1205937 · Cited by 346 · see citing works
Gallea, S., Lallemand, F., Atfi, A., Rawadi, G., Ramez, V., Spinella-Jaegle, S., Kawai, S., Faucheu, C., Huet, L., Baron, R., et al. (2001) · Bone · doi:10.1016/s8756-3282(01)00415-x · Cited by 303 · see citing works
Ghosh‐Choudhury, N., Abboud, S. L., Nishimura, R., Celeste, A. J., Mahimainathan, L., & Choudhury, G. G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205053200 · Cited by 299 · see citing works
Huang, H., Kim, H. J., Chang, E.-J., Lee, Z. H., Hwang, S. J., Kim, H.-M., Lee, Y.-K., & Kim, H. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.74 · Cited by 272 · see citing works
Self-citationPlexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis
Takegahara, N., Takamatsu, H., Toyofuku, T., Tsujimura, T., Okuno, T., Yukawa, K., Mizui, M., Yamamoto, M., Prasad, D. V., Suzuki, K., et al. (2006) · Nature Cell Biology · doi:10.1038/ncb1416 · Cited by 270 · see citing works
Hassan, M. Q., Tare, R. S., Lee, S. H., Mandeville, M., Morasso, M. I., Javed, A., van Wijnen, A. J., Stein, J. L., Stein, G. S., & Lian, J. B. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604508200 · Cited by 221 · see citing works
Akt promotes BMP2-mediated osteoblast differentiation and bone development
Mukherjee, A., & Rotwein, P. S. (2009) · Journal of Cell Science · doi:10.1242/jcs.042770 · Cited by 213 · see citing works
Kim, Y. J., Lee, M., Wozney, J. M., Cho, J., & Ryoo, H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404145200 · Cited by 202 · see citing works
Self-citationLee, M., Kim, Y.-J., Yoon, W., Kim, J.-I., Kim, B.-G., Hwang, Y., Wozney, J. M., Chi, X., Bae, S., Choi, K., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m502267200 · Cited by 198 · see citing works
Self-citationSuzuki, A., Guicheux, J., Palmer, G., et al. (2002) · Bone · doi:10.1016/s8756-3282(01)00660-3 · Cited by 187 · see citing works
Lifelong accumulation of bone in mice lacking Pten in osteoblasts
Liu, X., Bruxvoort, K. J., Diegel, C. R., Liu, J., Cichowski, R., Monier‐Faugere, M., Bouxsein, M., Wan, C., Williams, B. O., & Clemens, T. L. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604153104 · Cited by 173 · see citing works
Basile, J. R., Afkhami, T., & Gutkind, J. S. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.16.6889-6898.2005 · Cited by 145 · see citing works
Neuronal signaling and the regulation of bone remodeling
Elefteriou, F. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5175-3 · Cited by 127 · see citing works
p38 Regulates Expression of Osteoblast-specific Genes by Phosphorylation of Osterix
Ortuño, M. J., Ruiz-Gaspà, S., Rodríguez-Carballo, E., Susperregui, A. R. G., Bartrons, R., Rosa, J. L., & Ventura, F. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.123612 · Cited by 123 · see citing works
Activation of p38 and Smads mediates BMP-2 effects on human trabecular bone-derived osteoblasts
Nöth, U. A., Tuli, R., Seghatoleslami, R., Howard, M., Shah, A., Hall, D. J., Hickok, N. J., & Tuan, R. S. (2003) · Experimental Cell Research · doi:10.1016/s0014-4827(03)00386-0 · Cited by 116 · see citing works
CXC Chemokine Ligand 2 Induced by Receptor Activator of NF-κB Ligand Enhances Osteoclastogenesis
Ha, J., Choi, H.-S., Lee, Y., Kwon, H., Song, Y. W., & Kim, H. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902444 · Cited by 96 · see citing works
Self-citationp38 Mitogen-Activated Protein Kinase Regulates Osteoblast Differentiation through Osterix
Wang, X., Goh, C. H., & Li, B. (2006) · Endocrinology · doi:10.1210/en.2006-1000 · Cited by 93 · see citing works
Expression and function of semaphorin 7A in bone cells
Delorme, G., Saltel, F., Bonnelye, E., Jurdic, P., & Machuca‐Gayet, I. (2005) · Biology of the Cell · doi:10.1042/bc20040103 · Cited by 89 · see citing works
Assessing Bone Formation Using Mouse Calvarial Organ Cultures
Garrett, I. R. (2003) · Humana Press eBooks · doi:10.1385/1-59259-366-6:183 · Cited by 43 · see citing works
PlexinD1 deficiency induces defects in axial skeletal morphogenesis
Kanda, T., Yoshida, Y., Izu, Y., et al. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21306 · Cited by 27 · see citing works
Semaphorin pathways orchestrate osteogenesis
Tamagnone, L., & Giordano, S. (2006) · Nature Cell Biology · doi:10.1038/ncb0606-545 · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
A catalog of single nucleotide changes distinguishing modern humans from archaic hominins
Kuhlwilm, M., & Boeckx, C. (2019) · Scientific Reports · doi:10.1038/s41598-019-44877-x · Cited by 108 · see citing works
- Authors
- Oh, J.-E., Kim, H. J., Kim, W.-S., Lee, Z. H., Ryoo, H.-M., Hwang, S. J., Lee, Y., & Kim, H.-H.
- Affiliations
- Department of Biomedical Laboratory Science, Far East University, Chungbuk, Korea
- Seoul National University (KR)
- Corresponding author
- Kim, Hong-Hee
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-11-16
- Volume
- 27
- Issue
- 3
- Pages
- 552-562
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2011916385
- Cited by
- 21
- References
- 36
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 4 · 2018: 2 · 2016: 3 · 2015: 3 · 2013: 2
- FWCI
- 0.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Yale University
- 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
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Keywords
- Runx2, osteogenic differentiation, BMP2 signaling, bone anabolic therapy, osteoporosis, Smad signaling, Akt signaling, BMP type I receptor, BMP type II receptor, bone formation, mineralization
- MeSH terms
- Animals, Base Sequence, Cell Differentiation, Humans, Nerve Tissue Proteins, Osteoblasts, Receptors, Cell Surface, 3T3 Cells, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, RNA, Small Interfering, Core Binding Factor Alpha 1 Subunit, Mice, Bone Morphogenetic Protein 2, Real-Time Polymerase Chain Reaction
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
