Distal-less homeobox 5 is a master regulator of the osteogenesis of human mesenchymal stem cells
Open accessAbstract
Mesenchymal stem cells (MSCs) differentiate into multiple lineages and are a promising source of cells for clinical use. Previously, we found that the gene distal‑less homeobox 5 (DLX5) is specifically expressed in MSCs with osteogenic potential. Understanding the mechanism of osteogenesis is necessary for successful bone regeneration using MSCs. The aim of this study was to examine the function of the DLX5 gene in MSCs during osteogenesis (bone development). We analyzed the possible association between DLX5 expression and osteogenesis-, chondrogenesis- and adipogenesis-related gene expression in different cells isolated from bone marrow and cord blood. Differentiation capacity was assessed by observing morphological changes, monitoring gene expression patterns, and staining with Von Kossa, safranin O, and Oil Red O. Suppression of DLX5 expression by means of a small interfering RNA (siRNA) downregulated osteogenic markers and reduced the signs of calcium mineralization. Tanshinone IIA is a known small molecule activator of bone morphogenetic protein (BMP) signaling. Here, we report that induction of DLX5 by tanshinone IIA in MSCs enhanced osteogenic differentiation. In addition, we showed that tanshinone IIA (as a mediator of BMP2 signaling) activates runt-related transcription factor 2 (RUNX2) in MSCs and initiates calcium mineralization during osteogenesis. Taken together, these findings indicate that, in MSCs, DLX5 is a master regulator of osteogenesis. Furthermore, tanshinone IIA may be valuable for stem cell-based therapies of certain bone diseases.
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
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?
Multiple homeobox genes have been implicated in bone mass and osteogenesis regulation.
“Multiple homeobox genes have been implicated in the regulation of bone mass and osteogenesis16–19.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [18]
The Introduction (page unavailable) says homeobox-containing genes regulate skeletal development and that DLX genes function in osteoblast development; it also links DLX5 to osteogenesis. This supports the broad point about homeobox genes and osteogenesis, but the paper does not specifically address regulation of bone mass. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Regulation of osteoblast differentiation by transcription factors
Komori, T. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20958 · Cited by 1,027 · see citing works
Yamaguchi, A., Komori, T., & Suda, T. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.4.0403 · Cited by 688 · see citing works
HEO, J. S., CHOI, Y., KIM, H.-S., & KIM, H. O. (2016) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2015.2413 · Cited by 495 · see citing works
Self-citationSpecification of Jaw Subdivisions by Dlx Genes
Depew, M. J., Lufkin, T., & Rubenstein, J. L. R. (2002) · Science · doi:10.1126/science.1075703 · Cited by 468 · see citing works
Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5
Acampora, D., Merlo, G. R., Paleari, L., Zerega, B., Postiglione, M. P., Mantero, S., Bober, E., Barbieri, O., Simeone, A., & Levi, G. (1999) · Development · doi:10.1242/dev.126.17.3795 · Cited by 444 · see citing works
Robledo, R. F., Rajan, L., Li, X., & Lufkin, T. (2002) · Genes & Development · doi:10.1101/gad.988402 · Cited by 420 · see citing works
One strategy for cell and gene therapy: Harnessing the power of adult stem cells to repair tissues
Prockop, D. J., Gregory, C. A., & Spees, J. L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834138100 · Cited by 416 · 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-citationDlx5 regulates regional development of the branchial arches and sensory capsules
Depew, M. J., Liu, J. K., Long, J. E., Presley, R., Meneses, J. J., Pedersen, R. A., & Rubenstein, J. L. R. (1999) · Development · doi:10.1242/dev.126.17.3831 · Cited by 364 · see citing works
BMP2 signaling in bone development and repair
Rosen, V. (2009) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2009.10.018 · Cited by 333 · see citing works
Cell-Based Bone Tissue Engineering
Meijer, G. J., de Bruijn, J. D., Koole, R., et al. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040009 · Cited by 313 · see citing works
Ryoo, H., Hoffmann, H. M., Beumer, T. L., Frenkel, B., Towler, D. A., Stein, G. S., Stein, J. L., van Wijnen, A. J., & Lian, J. B. (1997) · Molecular Endocrinology · doi:10.1210/mend.11.11.0011 · Cited by 280 · see citing works
Cloning and characterization of two members of the vertebrate Dlx gene family.
Simeone, A., Acampora, D., Pannese, M., D’Esposito, M., Stornaiuolo, A., Gulisano, M., Mallamaci, A., Kastury, K., Druck, T., & Huebner, K. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.6.2250 · Cited by 277 · see citing works
Potential anticancer activity of tanshinone IIA against human breast cancer
Wang, X., Wei, Y., Yuan, S.-L., Liu, G., Lu, Y., Zhang, J., & Wang, W. (2005) · International Journal of Cancer · doi:10.1002/ijc.20880 · Cited by 237 · see citing works
Mesenchymal stem cells: heading into the clinic
Koç, O., & Lazarus, H. M. (2001) · Bone Marrow Transplantation · doi:10.1038/sj.bmt.1702791 · Cited by 206 · see citing works
Lee, 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
A BMP-Inducible Gene, Dlx5, Regulates Osteoblast Differentiation and Mesoderm Induction
Miyama, K., Yamada, G., Yamamoto, T. S., Takagi, C., Miyado, K., Sakai, M., Ueno, N., & Shibuyà, H. (1999) · Developmental Biology · doi:10.1006/dbio.1998.9197 · Cited by 196 · see citing works
Jang, S. I., Jeong, S.-I., Kim, K., et al. (2003) · Planta Medica · doi:10.1055/s-2003-45157 · Cited by 187 · see citing works
Reciprocal Regulation of Osteocalcin Transcription by the Homeodomain Proteins Msx2 and Dlx5
Newberry, E. P., Latifi, T. N., & Towler, D. A. (1998) · Biochemistry · doi:10.1021/bi981878u · Cited by 141 · see citing works
Ferrari, D. A., Sumoy, L., Gannon, J. L., et al. (1995) · Mechanisms of Development · doi:10.1016/0925-4773(95)98113-o · Cited by 100 · see citing works
BMP signals regulate Dlx5 during early avian skull development
Holleville, N., Quilhac, A., Bontoux, M., et al. (2003) · Developmental Biology · doi:10.1016/s0012-1606(03)00059-9 · Cited by 98 · see citing works
Defective Osteogenic Differentiation in the Development of Osteosarcoma
Wagner, E. R., Luther, G. A., Zhu, G., Luo, Q., Shi, Q., Kim, S. H., Gao, J., Huang, E., Gao, Y., Yang, K., et al. (2011) · Sarcoma · doi:10.1155/2011/325238 · Cited by 96 · see citing works
Overexpression of Dlx5 in Chicken Calvarial Cells Accelerates Osteoblastic Differentiation
Tadić, T., Dodig, M., Erceg, I., et al. (2002) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2002.17.6.1008 · Cited by 79 · see citing works
Inhibition of osteoclast differentiation by tanshinones from the root ofSalvia miltiorrhiza Bunge
Lee, S.-Y., Choi, D.-Y., & Woo, E. (2005) · Archives of Pharmacal Research · doi:10.1007/bf02973876 · Cited by 74 · see citing works
Self-citationMenard, C., & Tarte, K. (2013) · Stem Cell Research & Therapy · doi:10.1186/scrt214 · Cited by 71 · see citing works
Early onset of Runx2 expression caused craniosynostosis, ectopic bone formation, and limb defects
Maeno, T., Moriishi, T., Yoshida, C. A., Komori, H., Kanatani, N., Izumi, S., Takaoka, K., & Komori, T. (2011) · Bone · doi:10.1016/j.bone.2011.07.023 · Cited by 67 · see citing works
Zhang, Z., Song, Y., Zhang, X., et al. (2003) · Mechanisms of Development · doi:10.1016/j.mod.2003.09.002 · Cited by 61 · see citing works
Sohn, H. S., Heo, J. S., Kim, H., Choi, Y., & Kim, H. O. (2013) · Cytotherapy · doi:10.1016/j.jcyt.2012.10.015 · Cited by 55 · see citing works
Self-citationChen, X., Li, X., Wang, W., et al. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb56242.x · Cited by 46 · see citing works
Kim, H. J., & Kim, S. H. (2010) · Amino Acids · doi:10.1007/s00726-010-0557-8 · Cited by 39 · see citing works
Self-citationDlx and Other Homeobox Genes in the Morphological Development of the Dentition
Weiss, K. M., Ruddle, F. H., & Bollekens, J. A. (1995) · Connective Tissue Research · doi:10.3109/03008209509013703 · Cited by 38 · see citing works
Dlx5 regulation of mouse osteoblast differentiation mediated by avian retrovirus vector.
Erceg, I., Tadić, T., Kronenberg, M. S., et al. (2003) · PubMed · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ma, Q., Wang, S., Xue, H., Ni, L., Yuan, P., Shen, Y., Zheng, B., Wang, Q., Zhang, J., Wang, H., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61938-0 · Cited by 15 · see citing works
- Authors
- Heo, J. S., Lee, S. G., & Kim, H. O.
- Affiliations
- Korea University (KR)
- Severance Hospital (KR)
- Corresponding author
- Lee, Seung Gwan
- Kim, Hyun Ok
- Venue
- International Journal of Molecular Medicine
- Publisher
- Spandidos Publications
- Published
- 2017-09-19
- Volume
- 40
- Issue
- 5
- Pages
- 1486-1494
- ISSN
- 1107-3756 (ISSN-L)
- 1791-244X
- PMC
- PMC5627883
- OpenAlex
- W2756360505
- Cited by
- 43
- References
- 32
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 7 · 2018: 3
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- International Journal of Molecular Medicine (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Korea Health Industry Development Institute (HI15C0942)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
- Keywords
- Dlx5, mesenchymal stem cells, osteogenic differentiation, tanshinone IIA, BMP2 signaling, Runx2, calcium mineralization, chondrogenesis, adipogenesis, bone regeneration, siRNA knockdown, bone disease
- MeSH terms
- Cell Differentiation, Cell Survival, Cells, Cultured, Fetal Blood, Humans, Osteogenesis, Transcription Factors, Signal Transduction, Homeodomain Proteins, Gene Expression Regulation, Developmental, RNA Interference, RNA, Small Interfering, Abietanes, Bone Morphogenetic Protein 2, Mesenchymal Stem Cells
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
