Background Clinical and in vitro studies suggest that altered subchondral bone remodeling is involved in the progression and/or onset of osteoarthritis (OA). Human OA subchondral bone osteoblasts display an abnormal metabolism, including alterations in the Wnt/β-catenin signaling pathway.
Objectives As therapeutic strategies aimed at modifying the metabolism of subchondral bone may be indicated in the treatment of OA, we investigated diacerein, an anthraquinone, which has been shown to positively impact the abnormal subchondral bone metabolism in OA. Here, we further explored the effect of this drug, and its active metabolite rhein, on elements of the Wnt system in human OA subchondral bone osteoblasts.
Methods Therapeutic concentrations of diacerein/rhein (5-20 μg/ml) were used to assess their effects on the levels of β-catenin and the Wnt antagonists Dickkopf (DKK)-1 and -2. The β-catenin expression, as well as its nuclei translocation, was assessed after 20 hours of incubation using mRNA and Western blot. DKK-1 and -2 expressions were determined after 20 hours of incubation, and DKK-1 protein production after 48 hours in the culture medium using a specific ELISA.
Results The RNA level of β-catenin expression was increased in diacerein (p≤0.01) and rhein (p≤0.014) treated cells. For the β-catenin nuclei translocation, the Wnt ligand most potent in bone tissue was added at a concentration of 100 ng/ml, and increased this activity by only 50%. Both diacerein and rhein increased β-catenin nuclei translocation (diacerein, p≤0.04; rhein, p≤0.06). DKK-1 and DKK-2 mRNA expressions were dose-dependently decreased with both drugs (p≤0.009). Compared to DKK-1, the expression level of DKK-2 demonstrated a more marked decrease (90% vs. 60%). Both drugs also markedly and significantly decreased DKK-1 protein levels (p≤0.02) in a dose-dependent manner.
Conclusions Diacerein and rhein positively impact the abnormal Wnt system in OA by increasing the level of β-catenin in the nuclei. This effect is likely mediated via a decrease in the DKK-1 and -2. This study infers that these drugs may be appropriate for positively modulating the abnormal metabolism of human OA subchondral bone osteoblasts.
Disclosure of Interest None declared