Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling.

Abstract

Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation.

• Authors: Kentaro Miyamoto, Bisei Ohkawara, Mikako Ito, Akio Masuda, Akihiro Hirakawa, Tadahiro Sakai, Hideki Hiraiwa, Takashi Hamada, Naoki Ishiguro, Kinji Ohno
• Journal: PloS one (PLoS One) Vol. 12 Issue 9 Pg. e0184388 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28926590 (Publication Type: Journal Article)

Chemical References

• AXIN2 protein, human
• Axin Protein
• SOX9 Transcription Factor
• Serotonin Uptake Inhibitors
• Fluoxetine
• Matrix Metalloproteinase 13
• Lithium Chloride

Topics

• Animals
• Axin Protein (genetics, metabolism)
• Cartilage, Articular (drug effects, metabolism, pathology)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Chondrocytes (cytology, drug effects, metabolism)
• Chondrogenesis (drug effects)
• Disease Models, Animal
• Down-Regulation (drug effects)
• Fluoxetine (pharmacology, therapeutic use)
• Humans
• Lithium Chloride (toxicity)
• Matrix Metalloproteinase 13 (genetics, metabolism)
• Osteoarthritis (drug therapy, metabolism, pathology)
• Phosphorylation (drug effects)
• Rats
• Rats, Sprague-Dawley
• SOX9 Transcription Factor (genetics, metabolism)
• Selective Serotonin Reuptake Inhibitors (pharmacology, therapeutic use)
• Wnt Signaling Pathway (drug effects)