Abstract
Gadd45beta is known to be associated with cell growth control, apoptosis, and the cellular response to DNA damage. This gene is known to be mechanosensitive in chondrocytes under hydrostatic pressure. However, the expression and function in articular cartilage is not well understood. Here we review our recent findings on Gadd45beta expression and function in osteoarthritic cartilage. Gadd45beta was expressed at higher levels in cartilage from normal donors and patients with early osteoarthritis (OA) than in cartilage from patients with late-stage OA. In early OA, Gadd45beta was distributed variably in chondrocyte clusters, in middle and deep zone cells and in osteophytes. Gadd45beta down-regulated COL2A1 mRNA and promoter activity. Nf-κB overexpression increased Gadd45beta promoter activity, and siRNA Gadd45beta decreased cell survival per se and enhanced tumor necrosis factor α-induced cell death. Gadd45beta stimulated MMP-13 promoter activity through the JNK-mediated phosphorylation of JunD, partnered with fra2, in synergy with Runx 2. Gadd45beta enhanced Col10A1 transcription via the MTK1/MKK3/6/p38 axis and the activation of C/EBPβ-TAD4 in terminally differentiating chondrocytes. These findings suggest that Gadd45beta may play an important role in regulating chondrocyte homeostasis by modulating the collagen gene and promoting cell survival in normal cartilage and in early OA.
