THBS2 Marks Disease-Associated Chondrocyte States in Knee Osteoarthritis Cartilage: An Integrative Transcriptomic and Genetic Study.
- 1Department of Orthopedics, Beijing Chao-Yang Hospital, Capital Medical University, 5 JingYuan Road, Shijingshan District, Beijing 100043, China.
- 2Department of Clinical Laboratory, Beijing Shunyi District Hospital, No. 3 Guangming South Street, Shunyi District, Beijing 101300, China.
Abstract
Background/Objectives: Knee osteoarthritis (KOA) is a major cause of disability, yet the molecular links between extracellular matrix (ECM) remodeling, focal adhesion signaling, and pathological chondrocyte state transitions remain incompletely defined. We aimed to identify focal adhesion-related molecules associated with KOA and characterize their genetic, tissue-level, and single-cell features. Methods: Global Burden of Disease (GBD) 2021 data were used only to provide epidemiologic context for KOA-related disability-adjusted life years (DALYs). Bulk transcriptomic datasets (GSE114007 and GSE169077) were analyzed for differential expression, pathway enrichment, and focal adhesion-related genes. Two-sample Mendelian randomization (MR) integrating blood-derived cis-eQTL summary statistics from eQTLGen with KOA GWAS data was used for exploratory genetic prioritization; these eQTLs were not used as a surrogate measure of cartilage THBS2 expression. THBS2 was further evaluated by expression validation, gene set enrichment, immune-related ssGSEA signature analysis, single-cell RNA sequencing (GSE255460), Slingshot pseudotime analysis, and CellChat. Results: As epidemiologic context, global KOA related DALYs increased from 5.17 million in 1990 to 12.12 million in 2021. Bulk analysis identified 1584 differentially expressed genes (DEGs) and 32 focal adhesion-related candidates. Blood-derived cis-eQTL-based MR showed that genetically instrumented higher THBS2 expression was associated with lower KOA risk (OR = 0.718, 95% CI:0.570-0.905, p = 0.00497), whereas bulk transcriptomic analyses showed higher tissue-level THBS2 expression in KOA cartilage; this bulk difference may reflect both cell-composition changes and cell-intrinsic regulation. Single-cell analysis localized THBS2 mainly to fibrochondrocytes and osteogenic chondrocytes; At the pooled-cell level, THBS2-detectable cells were more frequent in OA than control cartilage (19.45% vs. 1.44%). Pooled CellChat analysis suggested differences in several communication pathways, including higher COLLAGEN, FN1, MIF, LAMININ, and SPP1 pathway scores but a lower THBS pathway score in OA. Conclusions: THBS2 is a genetically prioritized, disease-associated matricellular molecule linked to ECM remodeling and selected disease-associated chondrocyte states in KOA. The CellChat findings describe parallel, broader communication remodeling in the cartilage microenvironment.
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BibTeX
@article{hong2026thbs2,
title = {{THBS2 Marks Disease-Associated Chondrocyte States in Knee Osteoarthritis Cartilage: An Integrative Transcriptomic and Genetic Study.}},
author = {Gang Hong and Baodong Wang and Le Zhang and Xiaochuan Kong and Jiling Zhang and Tianyi Wang and Lei Zang},
journal = {Genes},
year = {2026},
month = oct,
doi = {10.3390/genes17101299},
url = {https://europepmc.org/article/MED/42938415},
note = {CC BY},
}
RIS
TY - JOUR
TI - THBS2 Marks Disease-Associated Chondrocyte States in Knee Osteoarthritis Cartilage: An Integrative Transcriptomic and Genetic Study.
AU - Gang Hong
AU - Baodong Wang
AU - Le Zhang
AU - Xiaochuan Kong
AU - Jiling Zhang
AU - Tianyi Wang
AU - Lei Zang
PY - 2026
DA - 2026/10/18
JO - Genes
DO - 10.3390/genes17101299
UR - https://europepmc.org/article/MED/42938415
AB - Background/Objectives: Knee osteoarthritis (KOA) is a major cause of disability, yet the molecular links between extracellular matrix (ECM) remodeling, focal adhesion signaling, and pathological chondrocyte state transitions remain incompletely defined. We aimed to identify focal adhesion-related molecules associated with KOA and characterize their genetic, tissue-level, and single-cell features. Methods: Global Burden of Disease (GBD) 2021 data were used only to provide epidemiologic context for KOA-related disability-adjusted life years (DALYs). Bulk transcriptomic datasets (GSE114007 and GSE169077) were analyzed for differential expression, pathway enrichment, and focal adhesion-related genes. Two-sample Mendelian randomization (MR) integrating blood-derived cis-eQTL summary statistics from eQTLGen with KOA GWAS data was used for exploratory genetic prioritization; these eQTLs were not used as a surrogate measure of cartilage THBS2 expression. THBS2 was further evaluated by expression validation, gene set enrichment, immune-related ssGSEA signature analysis, single-cell RNA sequencing (GSE255460), Slingshot pseudotime analysis, and CellChat. Results: As epidemiologic context, global KOA related DALYs increased from 5.17 million in 1990 to 12.12 million in 2021. Bulk analysis identified 1584 differentially expressed genes (DEGs) and 32 focal adhesion-related candidates. Blood-derived cis-eQTL-based MR showed that genetically instrumented higher THBS2 expression was associated with lower KOA risk (OR = 0.718, 95% CI:0.570-0.905, p = 0.00497), whereas bulk transcriptomic analyses showed higher tissue-level THBS2 expression in KOA cartilage; this bulk difference may reflect both cell-composition changes and cell-intrinsic regulation. Single-cell analysis localized THBS2 mainly to fibrochondrocytes and osteogenic chondrocytes; At the pooled-cell level, THBS2-detectable cells were more frequent in OA than control cartilage (19.45% vs. 1.44%). Pooled CellChat analysis suggested differences in several communication pathways, including higher COLLAGEN, FN1, MIF, LAMININ, and SPP1 pathway scores but a lower THBS pathway score in OA. Conclusions: THBS2 is a genetically prioritized, disease-associated matricellular molecule linked to ECM remodeling and selected disease-associated chondrocyte states in KOA. The CellChat findings describe parallel, broader communication remodeling in the cartilage microenvironment.
SN - 2073-4425
ER -