Dexamethasone enhances SOX9 expression in chondrocytes

Abstract

SOX9 is a transcription factor that activates type II procollagen (Col2a1) gene expression during chondrocyte differentiation. Glucocorticoids are also known to promote chondrocyte differentiation via unknown molecular mechanisms. We therefore investigated the effects of a synthetic glucocorticoid, dexamethasone (DEX), on Sox9 gene expression in chondrocytes prepared from rib cartilage of newborn mice. Sox9 mRNA was expressed at high levels in these chondrocytes. Treatment with DEX enhanced Sox9 mRNA expression within 24 h and this effect was observed at least up to 48 h. The effect of DEX was dose dependent, starting at 0·1 nM and maximal at 10 nM. The half life of Sox9 mRNA was approximately 45 min in the presence or absence of DEX. Western blot analysis revealed that DEX also enhanced the levels of SOX9 protein expression. Treatment with DEX enhanced Col2a1 mRNA expression in these chondrocytes and furthermore, DEX enhanced the activity of Col2-CAT (chloramphenicol acetyltransferase) construct containing a 1·6 kb intron fragment where chondrocytespecific Sry/Sox-consensus sequence is located. The enhancing effect of DEX was specific to SOX9, as DEX did not alter the levels of Sox6 mRNA expression. These data suggest that DEX promotes chondrocyte differentiation through enhancement of SOX9.

Differential effects of dexamethasone on the chondrogenesis of mesenchymal stromal cells: Influence of microenvironment, tissue origin and growth factor

“…They have been shown not only to inhibit the proliferation and differentiation of osteoblasts (Weinstein et al, 1998;Pereira et al, 2001), but also to promote the latter process, as well as to enhance alkaline-phosphatase activity and mineralization (Aubin, 1999;Jorgensen et al, 2004;Purpura et al, 2004). Likewise in the case of chondrocytes, glucocorticoids have been shown not only to promote the differentiation of these cells (Quarto et al, 1992) and their elaboration of a cartilaginous matrix (Kato and Gospodarowicz, 1985;Takano et al, 1985;Sekiya et al, 2001), but also to inhibit their growth and their expression of type-II collagen (Miyazaki et al, 2000). Published data are thus confl icting, and the actions of glucocorticoids are ill-defi ned.…”

<i>SOX</i> Gene Expression in Human Osteoarthritic Cartilage

“…It is known that SOX9 gene expression is influenced by many different signaling pathways. Proinflammatory cytokines like interleukin-1 alpha and tumor necrosis factor ␣ potently inhibit SOX9 expression, while bone morphogenetic proteins (BMP-2), fibroblast growth factor (FGF), glucocorticoids and Hedgehog signaling positively stimulate SOX9 transcription [20][21][22] . Thus, deregulation of SOX9 expression in osteoarthritic cartilage might well be explained by an imbalance of these signaling pathways in the degenerating tissue.…”

Effects of Chemotherapy on Bone Metabolism and Skeletal Growth

“…It is likely, however, that GCs also act as a stimulator of chondroprogenitor cell recruitment and supporter of chondrocyte viability since dexamethasone-treated ATDC5 cells in our study retained the capacity to re-enter chondrogenesis following withdrawal of GC. In support of this, dexamethasone stimulates expression of the Sox-9 transcription factor, which regulates expression of genes encoding markers of commitment to chondrogenesis, including Col2a1 and aggrecan [34]. Thus, although dexamethasone arrests growth and ATDC5 cell differentiation, the capacity for cells to undergo chondrogenesis is maintained in the presence of GC, when chondroprogenitor cells are quiescent, and the programme is re-activated when dexamethasone is removed.…”