LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis.
Manoj ArraGaurav SwarnkarKe KeJesse E OteroJun YingXin DuanTakashi MaruyamaMuhammad Farooq RaiRegis J O'KeefeGabriel MbalavieleJie ShenYousef Abu-AmerPublished in: Nature communications (2020)
The contribution of inflammation to the chronic joint disease osteoarthritis (OA) is unclear, and this lack of clarity is detrimental to efforts to identify therapeutic targets. Here we show that chondrocytes under inflammatory conditions undergo a metabolic shift that is regulated by NF-κB activation, leading to reprogramming of cell metabolism towards glycolysis and lactate dehydrogenase A (LDHA). Inflammation and metabolism can reciprocally modulate each other to regulate cartilage degradation. LDHA binds to NADH and promotes reactive oxygen species (ROS) to induce catabolic changes through stabilization of IκB-ζ, a critical pro-inflammatory mediator in chondrocytes. IκB-ζ is regulated bi-modally at the stages of transcription and protein degradation. Overall, this work highlights the function of NF-κB activity in the OA joint as well as a ROS promoting function for LDHA and identifies LDHA as a potential therapeutic target for OA treatment.
Keyphrases
- reactive oxygen species
- oxidative stress
- knee osteoarthritis
- dna damage
- extracellular matrix
- cell death
- signaling pathway
- rheumatoid arthritis
- lps induced
- transcription factor
- pi k akt
- nuclear factor
- human health
- genome wide
- single cell
- gene expression
- cell therapy
- cell proliferation
- quality improvement
- inflammatory response
- bone marrow
- protein protein
- small molecule
- smoking cessation