NFIA regulates articular chondrocyte fatty acid metabolism and joint homeostasis.

Abstract

Osteoarthritis (OA) is a joint disease with an etiology partially rooted in metabolic dysfunction, yet the underlying mechanisms in this context are not determined, limiting opportunities to develop therapeutic treatments. In this study, we used a multiomic approach combining RNA sequencing, ATAC-seq, MRE-seq, and metabolomics to reveal that OA articular chondrocytes induced by imbalanced transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling have increased fatty acid synthesis and oxidation processes regulated by nuclear factor I A (NFIA) up-regulation. Inhibition of <i>NFIA</i> suppressed the elevated gene expression of essential metabolic enzymes, including acetyl-CoA carboxylase A (<i>ACACA</i>) and carnitine palmitoyltransferase 2 (<i>CPT2</i>), leading to the restoration of fatty acid metabolism and cellular homeostasis in both murine and human OA articular chondrocytes. Obese mice displayed metabolic stress with elevated expression of NFIA, ACACA, and CPT2 in joint tissues, and they simultaneously developed profound synovitis, cartilage degeneration, subchondral bone sclerosis, and pain after joint injury. Both <i>Nfia</i> inhibition and pharmacological suppression of fatty acid metabolism in obese mice preserved joint integrity and mitigated synovitis and pain in the context of injury-induced OA settings. Overall, this work identifies a role for NFIA in the regulation of fatty acid metabolism and articular chondrocyte homeostasis and highlights fatty acid metabolism as a potential therapeutic target for OA treatment, particularly under obesity conditions.