Metabolic and Immune Pathways Drive Osteoclast Activation in Pigmented Villonodular Synovitis

According to findings from a proteomic and metabolomic analysis of synovial fluid samples, pigmented villonodular synovitis (PVNS), also known as tenosynovial giant cell tumor (TGCT), is driven by substantial metabolic reprogramming and immune-mediated osteoclast activation, offering new insight into the molecular mechanisms underlying this locally aggressive disease.

“The underlying molecular mechanisms of PVNS remain poorly understood, necessitating further research to uncover its pathogenesis and identify potential therapeutic targets,” stated Minghao Ge, MD, West China Hospital, Sichuan, China, and coauthors. “This study aims to investigate the pathological mechanisms of PVNS, focusing on the role of metabolic pathways, immune cell infiltration, and osteoclast differentiation in the progression of the disease.” 

In this study, synovial fluid samples from patients with PVNS underwent high-throughput proteomic and metabolomic profiling to identify differentially expressed proteins and metabolites contributing to disease progression. Pathway enrichment analysis and 2-way orthogonal partial least squares (O2PLS) modeling were used to characterize molecular interactions, and key findings were validated using Western blot assays.

Investigators identified 156 differentially expressed proteins and 62 differential metabolites in PVNS samples. Pathways related to osteoclast differentiation and nuclear factor–κB (NF-κB) survival signaling were significantly upregulated, with marked increases in Tumor Necrosis Factor Superfamily Member 11 (TNFSF11), Cathepsin K (CTSK), Adhesion G Protein–Coupled Receptor E5 (ADGRE5), and NF-κB. Metabolomic profiling further demonstrated enhanced linoleic acid metabolism and biosynthesis of unsaturated fatty acids, with elevated levels of 13-L-hydroperoxylinoleic acid and 13-OxoODE. Western blot validation confirmed the overexpression of ADGRE5, TNFSF11, CTSK, and NF-κB, suggesting coordinated activation of inflammatory, osteolytic, and metabolic pathways in promoting joint destruction. 

“This study highlights the critical role of metabolic adaptations and immune cell activity in the progression of PVNS,” concluded Dr Ge et al. “The findings suggest that targeting ADGRE5 and NF-κB could offer new therapeutic strategies for controlling disease progression and reducing joint destruction in PVNS patients.” 

Source: 

Ge M, Yang R, Xu B, et al. Proteomics and metabolomics studies in pigmented villonodular synovitis uncover the regulation of monocyte differentiation by the ADGRE5-NF-κB pathway. BMC Med. Published online: September 1, 2025. doi:10.1186/s12916-025-04358-7