Metabolic interactions between heme, thiol, and mitochondrial pathways in articular chondrocytes

Joint injuries often lead to posttraumatic osteoarthritis (PTOA), a condition driven by oxidative stress and mitochondrial dysfunction in cartilage cells. This dissertation explores detailed features of cartilage cell biology using carbon monoxide (CO) as a potential therapeutic gas with antioxidant properties, hypothesizing it may help reduce damage following joint injuries. CO activates an enzyme called heme oxygenase-1 (HO1), known to support joint health; however, safely delivering CO has been a challenge. We developed a carbon monoxide-containing foam (COF) that can be directly applied to joints, examining its effects on cellular health, redox balance, and mitochondrial function.

Our findings showed that COF quickly increased HO1 and mitochondrial-supporting proteins in chondrocytes, sustaining these protective effects for up to 12 h. COF also boosted mitochondrial respiration by 40% and improved antioxidant levels following injury. In animal models, COF remained in the joint for 24 h, significantly increased HO1 levels, displayed no toxicity, and enhanced cellular antioxidant levels, indicating its safety and effectiveness.

Further studies identified specific injury thresholds that could lead to mitochondrial dysfunction in cartilage. Additional studies revealed that high oxygen exposure, N-acetyl cysteine (NAC), and static electromagnetic fields (EMF), all have distinct effects upon cartilage redox outcomes. Together, these findings support that relationships between thiol, heme, and mitochondrial metabolic pathways are important for cartilage function.