Abstract
Chondrocyte hypertrophy, regulated by Runt-related transcription factor 2 (RUNX2) and matrix metalloproteinase 13 (MMP13), is a crucial step in cartilage degeneration and osteoarthritis (OA) pathogenesis. We previously demonstrated that microRNA-381 (miR-381) promotes MMP13 expression during chondrogenesis and contributes to cartilage degeneration; however, the mechanism underlying this process remained unclear. In this study, we observed divergent expression of miR-381 and histone deacetylase 4 (HDAC4), an enzyme that directly inhibits RUNX2 and MMP13 expression, during late-stage chondrogenesis of ATDC5 cells, as well as in prehypertrophic and hypertrophic chondrocytes during long bone development in E16.5 mouse embryos. We therefore investigated whether this miRNA regulates HDAC4 expression during chondrogenesis. Notably, overexpression of miR-381 inhibited HDAC4 expression but promoted RUNX2 expression. Moreover, transfection of SW1353 cells with an miR-381 mimic suppressed the activity of a reporter construct containing the 3′-untranslated region (3′-UTR) of HDAC4. Conversely, treatment with a miR-381 inhibitor yielded increased HDAC4 expression and decreased RUNX2 expression. Lastly, knockdown of HDAC4 expression resulted in increased RUNX2 and MMP13 expression in SW1353 cells. Collectively, our results indicate that miR-381 epigenetically regulates MMP13 and RUNX2 expression via targeting of HDAC4, thereby suggesting the possibilities of inhibiting miR-381 to control chondrocyte hypertrophy and cartilage degeneration.
Highlights
Osteoarthritis (OA), the most common disabling joint disease world-wide, is characterized by articular cartilage degeneration and subchondral bone remodeling
These findings indicate that histone deacetylase 4 (HDAC4) is a key regulator of chondrocyte hypertrophy and skeletal development [13]
Since miR-381 and HDAC4 are essential for mediating chondrocyte hypertrophy and cartilage degeneration, we hypothesized that miR-381 participates in OA pathogenesis by targeting and suppressing HDAC4 expression
Summary
Osteoarthritis (OA), the most common disabling joint disease world-wide, is characterized by articular cartilage degeneration and subchondral bone remodeling. Runt-related transcription factor 2 (RUNX2), a member of the RUNX family that promotes chondrocyte hypertrophy, endochondral ossification, and skeletal development [8,9], was shown to enhance MMP13 promoter activity and thereby promote cartilage degeneration [10,11]. HDAC4-null mice display early onset chondrocyte hypertrophy and subsequent premature ossification [13], and decreased expression of HDAC4 was found to contribute to the pathogenesis of cartilage degeneration in OA [17] Together, these findings indicate that HDAC4 is a key regulator of chondrocyte hypertrophy and skeletal development [13]. While miR-381 was observed to play an important role in cartilage degradation by enhancing MMP13 expression and repressing type II collagen (COL2A1) expression, we were unable to identify the target of this miRNA [25]. Since miR-381 and HDAC4 are essential for mediating chondrocyte hypertrophy and cartilage degeneration, we hypothesized that miR-381 participates in OA pathogenesis by targeting and suppressing HDAC4 expression
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