New research establishes the enzyme 4-aminobutyrate aminotransferase, mitochondrial (ABAT) as a key regulator of cellular metabolism and a potential therapeutic target in osteoarthritis (OA). The research also demonstrates that vigabatrin, a small-molecule inhibitor of ABAT that is already approved for clinical use as an anticonvulsant, prevents the development of OA in a mouse model of the disease.
Previous studies by the same group had revealed that genetic knockdown of the gene encoding DNA methyltransferase 3B (DNMT3B) in articular chondrocytes led to OA progression via changes in mitochondrial metabolism. In the current study, the group identified ABAT as an important downstream target of DNMT3B in chondrocytes and elucidated its role in regulating chondrocyte mitochondrial function and the development of OA.
“We found that loss of function of DNMT3B or gain of function of ABAT both lead to increased oxidative phosphorylation and a catabolic chondrocyte phenotype,” explains corresponding author Regis O’Keefe. “By contrast, gain of function of DNMT3B or loss of function of ABAT both reduce oxidative phosphorylation and result in an anabolic phenotype.”
Consistent with these findings, lentivirus-mediated overexpression of ABAT in mouse knees accelerated OA development following medial ligament injury (MLI) surgery, whereas lentiviral suppression of ABAT partially attenuated cartilage destruction. Notably, intraperitoneal administration of vigabatrin at a dose of 200 mg/kg for 6 weeks following MLI surgery completely prevented the development of injury-induced OA. In primary articular chondrocyte cell cultures, vigabatrin treatment also reduced mitochondrial respiration and inhibited IL-1β-mediated expression of catabolic genes including Runx2, Mmp13 and Col10a1.
“intraperitoneal administration of vigabatrin … completely prevented the development of injury-induced OA”
The investigators envisage that ABAT inhibition could be developed as a targeted therapy for OA, and are exploring the possibility of delivering ABAT small interfering RNA into arthritic joints via nanoparticles.
Shen, J. et al. Inhibition of 4-aminobutyrate aminotransferase protects against injury-induced osteoarthritis in mice. JCI Insight 4, e128568 (2019)