Highlights

  • Ɑ-ketoglutarate (AKG) reverses inflammation-induced stunted human cartilage cell growth.
  • AKG supplementation restores cartilage formation in an arthritis rat model.
  • AKG improves cartilage mitochondrial health by revamping gene activity for degradation of defective mitochondria (mitophagy) in arthritic rats.

Arthritis (osteoarthritis) affects over 32.5 million adults in the US and is characterized by severe joint pain and cartilage destruction. As the percentage of the population over age 60 grows, the number of people with osteoarthritis will likely increase. Since joint replacement is usually required for those with severe osteoarthritis, identifying ways to ameliorate this disease in its early stages requires urgency.

Published in Redox Biology, Ma and colleagues from Jishou University in China demonstrate that supplementing with the naturally occurring metabolite AKG restores the proliferation of osteoarthritic human cartilage cells. The molecule also increases the activity of genes for cartilage formation in an osteoarthritis rat model. The researchers go on to demonstrate that AKG improves cartilage cell health by increasing the activation of genes involved in the degradation of defective mitochondria – the power-generating structures within cells. These findings suggest that supplementing with AKG may be a way to ameliorate osteoarthritis, especially in its early stages.

AKG Restores Osteoarthritic Cartilage Cell Proliferation and Cartilage-Forming Gene Activation

To find how AKG affects osteoarthritic human cartilage cells, Ma and colleagues treated human cartilage cells with an osteoarthritis-inducing molecule interleukin-1ꞵ. The number of new cartilage cells that formed after interleukin-1ꞵ treatment was about cut in half compared to the proliferation of healthy cells. Adding AKG to the osteoarthritic cells restored their proliferation, suggesting that AKG may improve cartilage health by enhancing cartilage cell proliferation. Interestingly, adding the chemical Mdivi-1, which blocks defective mitochondria degradation, reversed AKG’s benefits, suggesting AKG is involved in disposing of defective mitochondria.

(Liu et al., 2023 | Redox Biology) ɑ-ketoglutarate restores osteoarthritic human cartilage cell proliferation. Exposing human cartilage cells to IL-1beta (IL-1beta) facilitates reduced proliferation (Positive Cells %) compared to normal cells (CON). Ɑ-ketoglutarate restores proliferation (IL-1beta+alpha-KG), but not in the presence of the inhibitor of defective mitochondria degradation Mdivi-1 (IL-1beta+alpha-KG+Mdivi), suggesting a role for this defective mitochondrial cleanup mechanism.

To find if AKG improves cartilage cells in the context of a living animal (in vivo), Ma and colleagues used a method called anterior cruciate ligament transection (ACLT) to induce osteoarthritis in a rat model. Essentially, the method involves cutting a ligament to induce inflammation and ultimately, osteoarthritis. Intriguingly, after the researchers performed ACLT in the rats, OARSI scores, an indicator of microscopic tissue damage, increased to about 10, indicating severe tissue damage. With AKG supplementation, OARSI scores diminished to about five, suggesting reduced arthritis and improved tissue health. The activity of genes involved in cartilage formation showed reduced levels, however, AKG restored their activity, also. These results suggest that osteoarthritis entails reduced gene activity associated with cartilage formation and that AKG restores this gene activity.

(Liu et al., 2023 | Redox Biology)ɑ-ketoglutarate restores cartilage and gene activity for cartilage formation in an osteoarthritic rat model. OARSI scores reflect the degree of microscopic tissue damage with a score of zero being normal and 10 reflecting severe damage. OARSI scores increased to about 10 with ACLT-induced arthritis (ACLT) compared to healthy cartilage (Sham), and ɑ-ketoglutarate (ACLT+ɑ-KG) reduced OARSI scores to about five. Gene activity (mRNA expression) for the cartilage formation genes ACAN (Figure C) and COL2A1 (Figure D) diminished in ACLT-induced osteoarthritic rats, but ɑ-ketoglutarate restored their activation.

The human cartilage cell findings pointed to the degradation of defective mitochondria involved in AKG benefits against osteoarthritis. As such, Ma and colleagues sought to find whether AKG affects defective mitochondria degradation in the osteoarthritic rat model. The China-based research team found that ACLT-induced osteoarthritis reduced gene activity for proteins involved in defective mitochondria degradation (mitophagy), but that AKG restored their activity. These data suggest that AKG acts, in part, by increasing the cleanup of defective mitochondria, which should have the effect of improving overall mitochondrial health.

(Liu et al., 2023 | Redox Biology)ɑ-ketoglutarate restores defective mitochondrial degradation gene activation in osteoarthritic rats. Two proteins involved in defective mitochondria degradation – PINK1 (Figure D) and Parkin (Figure E) – show reduced gene activation with ACLT-induced arthritis. Ɑ-ketoglutarate restored osteoarthritic rat PINK1 and PARKIN gene activity (mRNA expression).

“In a nutshell, our findings provided hitherto undocumented evidence of the role of [AKG] in maintaining cartilage homeostasis, suggesting it can be a potential therapeutic target and medication for [osteoarthritis],” say Ma and colleagues.

Alleviating Early-Stage Osteoarthritis with AKG

The finding that AKG likely improves mitochondrial health by enhancing the degradation of defective mitochondria is interesting. Defective mitochondria produce harmful, oxygen-containing molecules (reactive oxygen species) that contribute to cellular dysfunction. By improving mitochondrial health, AKG could thereby help rid cells of reactive oxygen species.

While not many treatments exist for osteoarthritis other than improving exercise habits, the possibility that AKG may work against this disease comes as welcome news. Future studies of AKG’s benefits against osteoarthritis may include clinical trials to find if the supplement works to improve joint health in humans. One can obtain AKG as a supplement for $22 to $25 for a month’s supply.