Regulation of Human Chondrocyte Function through Direct Inhibition of Cartilage Master Regulator SOX9 by MicroRNA-145 (miRNA-145)

• Published in: The Journal of biological chemistry Vol. 287; no. 2; pp. 916 - 924
• Main Authors: Martinez-Sanchez, Aida, Dudek, Katarzyna A., Murphy, Chris L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.01.2012; American Society for Biochemistry and Molecular Biology
• Subjects: 3' Untranslated Regions - genetics; Aggrecans - biosynthesis; Aggrecans - genetics; Animals; Campomelic Dysplasia - genetics; Campomelic Dysplasia - metabolism; Campomelic Dysplasia - pathology; Cartilage Biology; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Cell Biology; Cell Differentiation; Cells, Cultured; Chondrocytes - metabolism; Chondrocytes - pathology; Collagen Type II - biosynthesis; Collagen Type II - genetics; Gene Expression Regulation; Humans; Hypertrophy; Hypoxia-inducible Factor (HIF); Mice; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; miR-145; miR-675; Molecular cell biology; Mutation; SOX9; SOX9 Transcription Factor - biosynthesis; SOX9 Transcription Factor - genetics; miR-675; MicroRNA; Cartilage Biology; miR-145; Hypoxia-inducible Factor (HIF); Cell Differentiation; Molecular cell biology; SOX9; Hypertrophy
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M111.302430

Articular cartilage enables weight bearing and near friction-free movement in the joints. Critical to its function is the production of a specialized, mechanocompetent extracellular matrix controlled by master regulator transcription factor SOX9. Mutations in SOX9 cause campomelic dysplasia, a haploinsufficiency disorder resulting in severe skeletal defects and dwarfism. Although much is understood about how SOX9 regulates cartilage matrix synthesis and hence joint function, how this master regulator is itself regulated remains largely unknown. Here we identify a specific microRNA, miR-145, as a direct regulator of SOX9 in normal healthy human articular chondrocytes. We show that miR-145 directly represses SOX9 expression in human cells through a unique binding site in its 3′-UTR not conserved in mice. Modulation of miR-145 induced profound changes in the human chondrocyte phenotype. Specifically, increased miR-145 levels cause greatly reduced expression of critical cartilage extracellular matrix genes (COL2A1 and aggrecan) and tissue-specific microRNAs (miR-675 and miR-140) and increased levels of the hypertrophic markers RUNX2 and MMP13, characteristic of changes occurring in osteoarthritis. We propose miR-145 as an important regulator of human chondrocyte function and a new target for cartilage repair. Background: SOX9 is essential for cartilage. Results: miR-145 directly targets SOX9, and increased miR-145 levels reduce expression of SOX9 and the extracellular matrix genes critical to cartilage function. Conclusion: SOX9 is subject to significant post-transcriptional regulation by miR-145 in human chondrocytes. Significance: Our data give new insights into the mechanisms regulating SOX9 and identify miR-145 as a new target for cartilage repair.