Abstract
Background
This study aimed to investigate the expression levels and relationship of bone morphogenetic
proteins (BMPs) signaling molecules and microRNA-140 (miR-140) in human osteoarthritis
(OA) chondrocytes.
Materials and Methods
Different stage chondrocytes (normal cartilage, mid-stage OA and advanced-stage OA)
were isolated from cartilage samples according to Kellgren and Lawrence criteria.
The effect of miR-140 on BMPs signaling was evaluated by transfecting miR-140 mimic
or inhibitor into chondrocytes. The expression of responsive genes was measured using
real-time polymerase chain reaction and Western blotting analysis.
Results
There was a significant reduction in miR-140 and SOX9 expression in OA groups compared
to the normal group, and there was a further reduction in the severe OA group compared
to the moderate OA group. Compared with the normal group, the expression of ALK1,
SMAD1, COL10A1 and MMP3 was higher in the OA groups, whereas the expression of COL2A1
was lower in the OA groups. In the moderate OA group, transfection with miR-140 mimic
increased SMAD1, SOX9 and COL2A1 expression, but decreased COL10A1 expression. However,
there was an opposite effect after transfecting miR-140 inhibitor with decreased SMAD1,
SOX9 and COL2A1 expression, and increased COL10A1 expression. Interestingly, the biological
effect of transfecting miR-140 mimic or inhibitor was similar in the severe OA group.
SMAD1 and COL2A1 protein production followed the same pattern as their expression
profile.
Conclusions
miR-140 suppresses chondrocytes hypertrophy by controlling the BMPs signaling pathway,
which highlights the importance of miR-140 in the maintenance of chondrocyte homeostasis
and opens up novel avenues in OA therapeutic strategies.
Key Indexing Terms
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References
- Chondrocyte hypertrophy and osteoarthritis: role in initiation and progression of cartilage degeneration?.Osteoarthritis Cartilage. 2012; 20: 223-232
- Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders.Arthritis Res Ther. 2010; 12: 216
- Update on the biology of the chondrocyte and new approaches to treating cartilage diseases.Best Pract Res Clin Rheumatol. 2006; 20: 1003-1025
- Growth factor transgenes interactively regulate articular chondrocytes.J Cell Biochem. 2013; 114: 908-919
- Insights on biology and pathology of HIF-1alpha/-2alpha, TGFbeta/BMP, Wnt/beta-catenin, and NF-kappaB pathways in osteoarthritis.Curr Pharm Des. 2012; 18: 3293-3312
- Controlling cell fate by bone morphogenetic protein receptors.Mol Cell Endocrinol. 2003; 211: 105-113
- TGF-b signaling in cartilage homeostasis and osteoarthritis.Front Biosci (Schol Ed). 2012; 4: 251-268
- Localization of bone morphogenetic protein-2 in human osteoarthritic cartilage and osteophyte.Osteoarthritis Cartilage. 2003; 11: 278-284
- Elevated extracellular matrix production and degradation upon bone morphogenetic protein-2 (BMP-2) stimulation point toward a role for BMP-2 in cartilage repair and remodeling.Arthritis Res Ther. 2007; 9: R102
- Activation of WNT and BMP signaling in adult human articular cartilage following mechanical injury.Arthritis Res Ther. 2006; 8: R139
- Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation.J Bone Miner Res. 2006; 21: 4-16
- Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis.Arthritis Rheum. 2006; 54: 3533-3544
- MicroRNAs expression profile in solid and unicystic ameloblastomas.PLoS One. 2017; 12: e0186841
- MicroRNA expression in zebrafish embryonic development.Science (New York, NY). 2005; 309: 310-311
- MicroRNA-140 plays dual roles in both cartilage development and homeostasis.Genes Dev. 2010; 24: 1173-1185
- MicroRNA-29b contributes to collagens imbalance in human osteoarthritic and dedifferentiated articular chondrocytes.Biomed Res Int. 2017; 2017: 9792512
- MicroRNA-483-5p modulates the expression of cartilage-related genes in human chondrocytes through down-regulating TGF-beta1 expression.Tohoku J Exp Med. 2017; 243: 41-48
- MicroRNA-218-5p as a potential target for the treatment of human osteoarthritis molecular therapy.Mol Ther. 2017; 25: 2676-2688
- Differences in vertebrate microRNA expression.Proc Natl Acad Sci U S A. 2006; 103: 14385-14389
- New evidence supports the notion that microRNA-140 may play a role in the early stages of bone development.Arthritis Rheum. 2013; 65: 1668-1669
- MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses.Arthritis Rheum. 2009; 60: 2723-2730
- MicroRNA-140 expression during chondrogenic differentiation of equine cord blood-derived mesenchymal stromal cells.Stem Cells Dev. 2013; 22: 1288-1296
- microRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN.Stem Cells Dev. 2014; 23: 290-304
- Radiological assessment of osteo-arthrosis.Ann Rheum Dis. 1957; 16: 494-502
- Interleukin-11, an inducible cytokine in human articular chondrocytes and synoviocytes, stimulates the production of the tissue inhibitor of metalloproteinases.J Biol Chem. 1993; 268: 21527-21532
- MicroRNA-30a promotes extracellular matrix degradation in articular cartilage via downregulation of Sox9.Cell Prolif. 2016; 49: 207-218
- SOX gene expression in human osteoarthritic cartilage Pathobiology.Pathobiology. 2008; 75: 195-199
- Correlation between gene expression and osteoarthritis progression in human.Int J Mol Sci. 2016; 17: 1126
- Gene expression in human chondrocytes in late osteoarthritis is changed in both fibrillated and intact cartilage without evidence of generalised chondrocyte hypertrophy.Ann Rheum Dis. 2010; 69: 234-240
- Quantification of expression levels of cellular differentiation markers does not support a general shift in the cellular phenotype of osteoarthritic chondrocytes.J Orthop Res. 2003; 21: 96-101
- The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells.FEBS Lett. 2006; 580: 4214-4217
- Regulation of the IGFBP-5 and MMP-13 genes by the microRNAs miR-140 and miR-27a in human osteoarthritic chondrocytes.BMC Musculoskelet Disord. 2009; 10: 148
- mRNA expression profiling reveals conserved and non-conserved miR-140 targets.RNA Biol. 2011; 8: 607-615
- Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo.Proc Natl Acad Sci U S A. 2005; 102: 5062-5067
- BMPs are required at two steps of limb chondrogenesis: formation of prechondrogenic condensations and their differentiation into chondrocytes.Dev Biol. 2000; 219: 237-249
- Hypertrophic differentiation during chondrogenic differentiation of progenitor cells is stimulated by BMP-2 but suppressed by BMP-7.Osteoarthritis Cartilage. 2013; 21: 604-613
- Effects of intermittent hydrostatic pressure and BMP-2 on osteoarthritic human chondrocyte metabolism in vitro.J Orthop Res. 2011; 29: 361-368
- Bone morphogenetic protein-2-induced Wnt/beta-catenin signaling pathway activation through enhanced low-density-lipoprotein receptor-related protein 5 catabolic activity contributes to hypertrophy in osteoarthritic chondrocytes.Arthritis Res Ther. 2012; 14: R82
- Matrilin-3 inhibits chondrocyte hypertrophy as a bone morphogenetic protein-2 antagonist.J Biol Chem. 2014; 289: 34768-34779
- let-7 and miR-140 microRNAs coordinately regulate skeletal development.Proc Natl Acad Sci U S A. 2013; 110: E3291-E3300
- Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks.PloS one. 2008; 3: e3740
- The expression and function of microRNAs in chondrogenesis and osteoarthritis.Arthritis Rheum. 2012; 64: 1909-1919
- MicroRNA-140 promotes adipocyte lineage commitment of C3H10T1/2 pluripotent stem cells via targeting osteopetrosis-associated transmembrane protein 1.J Biol Chem. 2013; 288: 8222-8230
- SOX9 directly binds CREB as a novel synergism with the PKA pathway in BMP-2-induced osteochondrogenic differentiation.J Bone Miner Res. 2009; 24: 826-836
- Accelerated up-regulation of L-Sox5, Sox6, and Sox9 by BMP-2 gene transfer during murine fracture healing.J Bone Miner Res. 2001; 16: 1837-1845
- Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling.Mol Cell Biol. 2011; 31: 3019-3028
- MicroRNA signatures in human cancers.Nat Rev Cancer. 2006; 6: 857-866
- Reciprocal effects between microRNA-140-5p and ADAM10 suppress migration and invasion of human tongue cancer cells.Biochem Biophys Res Commun. 2014; 448: 308-314
Article info
Publication history
Accepted:
January 18,
2018
Received in revised form:
January 6,
2018
Received:
August 30,
2017
Footnotes
☆This study was supported by funding from the National Natural Science Foundation of China (No. 81672219); the Science and Technology Support Program of Sichuan Province (No. 2014SZ0023-2) and the Project of International Cooperation of Sichuan Province (No. 2016HH0071).
☆☆The authors have no conflicts of interest to disclose.
Identification
Copyright
© 2018 Southern Society for Clinical Investigation. Published by All rights reserved.
