Chondrocyte-Specific MicroRNA-140 Regulates Endochondral Bone Development and Targets Dnpep To Modulate Bone Morphogenetic Protein Signaling
Open accessAbstract
MicroRNAs (miRNAs) play critical roles in a variety of biological processes in diverse organisms, including mammals. In the mouse skeletal system, a global reduction of miRNAs in chondrocytes causes a lethal skeletal dysplasia. However, little is known about the physiological roles of individual miRNAs in chondrocytes. The miRNA-encoding gene, Mir140, is evolutionarily conserved among vertebrates and is abundantly and almost exclusively expressed in chondrocytes. In this paper, we show that loss of Mir140 in mice causes growth defects of endochondral bones, resulting in dwarfism and craniofacial deformities. Endochondral bone development is mildly advanced due to accelerated hypertrophic differentiation of chondrocytes in Mir140-null mice. Comparison of profiles of RNA associated with Argonaute 2 (Ago2) between wild-type and Mir140-null chondrocytes identified Dnpep as a Mir140 target. As expected, Dnpep expression was increased in Mir140-null chondrocytes. Dnpep overexpression showed a mild antagonistic effect on bone morphogenetic protein (BMP) signaling at a position downstream of Smad activation. Mir140-null chondrocytes showed lower-than-normal basal BMP signaling, which was reversed by Dnpep knockdown. These results demonstrate that Mir140 is essential for normal endochondral bone development and suggest that the reduced BMP signaling caused by Dnpep upregulation plays a causal role in the skeletal defects of Mir140-null mice.
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Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice.
“Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6.”
From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [6]
The section ‘Mir140-null mice show defects in endochondral bone growth’ describes skeletal abnormalities in Mir140-null mice. But the paper describes a Mir140 deletion, not mice with the claimed single-nucleotide substitution; our copy does not report patient abnormalities or compare substitution-bearing mice with null mice. (LLM, conf=0.78)
Experimental — accuracy not yet measuredLoss of miR-140, encoded by Mir140, in mice leads to short stature and craniofacial abnormalities.
“loss of miR-140, encoded by Mir140, in mice leads to short stature and craniofacial abnormalities6,16”
From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [6]
The miR-140-null phenotype included mildly advanced terminal differentiation of growth plate chondrocytes of developing bones.
“This miR-140-null phenotype included mildly advanced terminal differentiation of growth plate chondrocytes of developing bones6,17.”
From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [6]
miR-140-null mice were previously described.
“miR-140-null mice were previously described6.”
From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [6]
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Research works printed but not linked: 5
- Eggan, K., et al. 2001. Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc. Natl. Acad. Sci. U. S. A. 98:6209-6214.
- Karginov, F. V., et al. 2007. A biochemical approach to identifying mi- croRNA targets. Proc. Natl. Acad. Sci. U. S. A. 104:19291-19296.
- Kobayashi, T., et al. 2008. Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. Proc. Natl. Acad. Sci. U. S. A. 105:1949- 1954.
- Murtaugh, L. C., L. Zeng, J. H. Chyung, and A. B. Lassar. 2001. The chick VOL. 31, 2011 Mir140 IN CHONDROCYTES 3027 transcriptional repressor Nkx3.2 acts downstream of Shh to promote BMP- dependent axial chondrogenesis. Dev. Cell 1:411-422.
- Yoon, B. S., et al. 2005. Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc. Natl. Acad. Sci. U. S. A. 102:5062-5067.
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Gain-of-function mutation of microRNA-140 in human skeletal dysplasia
Grigelioniene, G., Suzuki, H. I., Taylan, F., Mirzamohammadi, F., Borochowitz, Z. U., Ayturk, U. M., Tzur, S., Horemuzova, E., Lindstrand, A., Weis, M. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0353-2 · Cited by 103 · see citing works
“…evolutionarily conserved cell type-specific function 11–13 . miR-140-5p and miR-140-3p (collectively miR-140) are abundantly and relatively specifically expressed in chondrocytes 14,15 , and loss of miR-140, encoded by Mir140, in mice leads to short stature and craniofacial abnormalities 6,16 .”
InfluentialSelf-citation
- Authors
- Nakamura, Y., Inloes, J. B., Katagiri, T., & Kobayashi, T.
- Affiliations
- Murayama Medical Center (JP)
- Harvard University (US)
- Saitama Medical University (JP)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2011-07-01
- Volume
- 31
- Issue
- 14
- Pages
- 3019-3028
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3133397
- OpenAlex
- W2123345024
- Cited by
- 170
- References
- 0
- Citations by year
- 2025: 12 · 2024: 12 · 2023: 10 · 2022: 7 · 2021: 5 · 2020: 15 · 2019: 8 · 2018: 10 · 2017: 7 · 2016: 15 · 2015: 21 · 2014: 20 · 2013: 11 · 2012: 11
- FWCI
- 11.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Beth Israel Deaconess Medical Center
- American Society for Bone and Mineral Research
- National Institutes of Health
- Japan Society for the Promotion of Science (21390423)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR054500, R01AR056645, AR054500, AR056645)
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- microRNA-140, chondrocytes, endochondral bone development, BMP signaling, Smad, chondrocyte hypertrophy, dwarfism, craniofacial deformities, Argonaute 2, skeletal dysplasia, microRNA target regulation
- MeSH terms
- Animals, Bone Development, Cell Differentiation, Cells, Cultured, Signal Transduction, Mice, Knockout, Bone Morphogenetic Proteins, Chondrocytes, Receptor, Platelet-Derived Growth Factor alpha, MicroRNAs, Glutamyl Aminopeptidase, Mice, Smad Proteins
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