Endothelial regulators in the infrapatellar fat pad of osteoarthritis revealed by integrative multi-omics and genetic causal inference.
5 affiliations
- 1Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. [email protected].
- 2Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. [email protected].
- 3Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- 4Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. [email protected].
- 5Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. [email protected].
Abstract
Osteoarthritis (OA) is a multifactorial degenerative joint disease involving multiple joint components, including the infrapatellar fat pad (IFP), whose role in OA pathogenesis remains poorly understood. In this study, we employed an integrative multi-omics strategy to delineate the cellular and molecular landscape of the IFP in OA. Using single-nucleus RNA sequencing (snRNA-seq) data, we identified endothelial cells as key mediators within the IFP microenvironment, exhibiting strong intercellular communication. Differentially expressed genes (DEGs) from endothelial cells were subjected to Mendelian randomization (MR) analysis, integrating expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and genome-wide association study (GWAS) datasets. This analysis revealed family with sequence similarity 241 member A (FAM241A) and thymidine kinase 2 (TK2) as endothelial-specific causal regulators of OA, with FAM241A associated with a protective effect and TK2 with increased disease risk. Pathway analyses suggested distinct biological roles for FAM241A and TK2. Both genes demonstrated progressively increased expression along pseudotime trajectories. Spatial transcriptomics (ST) revealed region-specific expression patterns, further supporting their involvement in IFP remodeling. Collectively, this study identifies FAM241A and TK2 as novel endothelial-specific causal genes in the IFP of OA, and uncovers temporally and spatially regulated transcriptional programs. These findings provide new mechanistic insights into OA pathogenesis and propose promising targets for biomarker development and therapeutic intervention.
Related
- Ultrasonographic evaluation of fibrous structure and mechanical characteristics of the infrapatellar fat pad in female patients with knee osteoarthritis: a cross-sectional study.
- High-throughput screen identifies metabolite regulators of endothelial function
- Microcystin-LR exposure induces cartilage degeneration and dysregulates osteoarthritis-associated targets: an integrative computational and experimental study
- Identification of transcriptomic signatures associated with an ac4C related gene set and candidate expression based clusters in osteoarthritis through integrative bioinformatics
- Extracellular Matrix Remodeling and Glycoprotein Biomarkers Across Osteoarthritis, Rheumatoid Arthritis, and Temporomandibular Disorders: A Systematic Review and Integrative Analysis
BibTeX
@article{li2026endothelial,
title = {{Endothelial regulators in the infrapatellar fat pad of osteoarthritis revealed by integrative multi-omics and genetic causal inference.}},
author = {Guanzhi Li and Xiao Deng and Zikun Xie and Mingsheng Xie},
journal = {Cellular and molecular life sciences : CMLS},
year = {2026},
month = jul,
doi = {10.1007/s00018-026-06365-0},
url = {https://europepmc.org/article/MED/42957875},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Endothelial regulators in the infrapatellar fat pad of osteoarthritis revealed by integrative multi-omics and genetic causal inference.
AU - Guanzhi Li
AU - Xiao Deng
AU - Zikun Xie
AU - Mingsheng Xie
PY - 2026
DA - 2026/07/31
JO - Cellular and molecular life sciences : CMLS
DO - 10.1007/s00018-026-06365-0
UR - https://europepmc.org/article/MED/42957875
AB - Osteoarthritis (OA) is a multifactorial degenerative joint disease involving multiple joint components, including the infrapatellar fat pad (IFP), whose role in OA pathogenesis remains poorly understood. In this study, we employed an integrative multi-omics strategy to delineate the cellular and molecular landscape of the IFP in OA. Using single-nucleus RNA sequencing (snRNA-seq) data, we identified endothelial cells as key mediators within the IFP microenvironment, exhibiting strong intercellular communication. Differentially expressed genes (DEGs) from endothelial cells were subjected to Mendelian randomization (MR) analysis, integrating expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and genome-wide association study (GWAS) datasets. This analysis revealed family with sequence similarity 241 member A (FAM241A) and thymidine kinase 2 (TK2) as endothelial-specific causal regulators of OA, with FAM241A associated with a protective effect and TK2 with increased disease risk. Pathway analyses suggested distinct biological roles for FAM241A and TK2. Both genes demonstrated progressively increased expression along pseudotime trajectories. Spatial transcriptomics (ST) revealed region-specific expression patterns, further supporting their involvement in IFP remodeling. Collectively, this study identifies FAM241A and TK2 as novel endothelial-specific causal genes in the IFP of OA, and uncovers temporally and spatially regulated transcriptional programs. These findings provide new mechanistic insights into OA pathogenesis and propose promising targets for biomarker development and therapeutic intervention.
SN - 1420-682X
SN - 1420-9071
ER -