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Mir-374-5p, mir-379-5p, and mir-503-5p regulate proliferation and hypertrophic differentiation of growth plate chondrocytes in male rats
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States.
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States.
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States.
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States.
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2018 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 159, no 3, p. 1469-1478Article in journal (Refereed) Published
Abstract [en]

Growth plate chondrocytes undergo sequential differentiation to form the resting (RZ), proliferative (PZ), and hypertrophic zones (HZ). The important role of microRNAs (miRNAs) in the growth plate was previously revealed by cartilage-specific ablation of Dicer, an enzyme essential for biogenesis of many miRNAs. To identify specific miRNAs that regulate differentiation of PZ chondrocytes to HZ chondrocytes, we microdissected individual growth plate zones from juvenile rats and performed miRNA profiling using a solution hybridization method and also miRNA-seq. Thirty-four miRNAs were differentially expressed between PZ and HZ and we hypothesized that some of the miRNAs that are preferentially expressed in PZ may serve to promote proliferation and inhibit hypertrophic differentiation. Consistent with this hypothesis, transfection of inhibitors for four of these miRNAs (mir-369-3p, mir-374-5p, mir-379-5p, mir-503-5p) decreased proliferation in primary epiphyseal chondrocytes. The inhibitors for three of these miRNAs (mir-374-5p, mir-379-5p, mir-503-5p) also increased expression of multiple genes that are associated with chondrocyte hypertrophic differentiation. We next hypothesized that preferential expression of these miRNAs in PZ is driven by the PTHrP concentration gradient across the growth plate. Consistent with this hypothesis, treatment of primary chondrocytes with a PTH/PTHrP receptor agonist, PTH1-34, increased expression of mir-374-5p, mir-379-5p, and mir-503-5p. Taken together, our findings suggest that the PTHrP concentration gradient across the growth plate induces differential expression of mir-374-5p, mir-379-5p and mir-503-5p between PZ and HZ. In PZ, the higher expression levels of these miRNAs promote proliferation and inhibit hypertrophic differentiation. In HZ, downregulation of these miRNAs inhibits proliferation and promotes hypertrophic differentiation.

Place, publisher, year, edition, pages
Cary, NC, USA: Oxford University Press, 2018. Vol. 159, no 3, p. 1469-1478
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:oru:diva-64843DOI: 10.1210/en.2017-00780ISI: 000430710400019PubMedID: 29390136Scopus ID: 2-s2.0-85042671241OAI: oai:DiVA.org:oru-64843DiVA, id: diva2:1181004
Funder
Swedish Research Council, K2015-54X-22 736-01-4 2015-02227VINNOVA, 2014-01438Marianne and Marcus Wallenberg FoundationNovo Nordisk
Note

Funding Agencies:

Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development  

Intramural Research Program of the National Human Genome Research Institute  

Common Fund of the National Institutes of Health

Stockholm County Council  

Byggmästare Olle Engkvist Stiftelse 

Sallskapet Barnavard  

Stiftelsen Frimurare Barnhuset i Stockholm  

Karolinska Institutet, Stockholm, Sweden  

Örebro University, Örebro, Sweden 

Available from: 2018-02-07 Created: 2018-02-07 Last updated: 2018-09-04Bibliographically approved

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