2. Academic Validation
  3. Identification and validation of transcriptome-wide association study-derived genes as potential druggable targets for osteoarthritis

Identification and validation of transcriptome-wide association study-derived genes as potential druggable targets for osteoarthritis

  • Bone Joint Res. 2025 Mar 13;14(3):224-235. doi: 10.1302/2046-3758.143.BJR-2024-0251.R1.
Xindie Zhou 1 2 3,  Xinjian Ye 4 5,  Jiapei Yao 1 2,  Xiaolong Lin 4 5,  Yiping Weng 1 2,  Yong Huang 1 2,  Yaojun Lu 1 2,  JingJing Shang 6,  Luming Nong 1 2
Affiliations

Affiliations

  • 1 Department of Orthopedics, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China.
  • 2 Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
  • 3 Department of Orthopedics, Gonghe County Hospital of Traditional Chinese Medicine, Hainan Tibetan Autonomous Prefecture, Qinghai, China.
  • 4 Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China.
  • 6 Department of Pharmacy, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China.
PMID: 40079200 DOI: 10.1302/2046-3758.143.BJR-2024-0251.R1
Abstract

Aims: Osteoarthritis (OA) is a widespread chronic degenerative joint disease with an increasing global impact. The pathogenesis of OA involves complex interactions between genetic and environmental factors. Despite this, the specific genetic mechanisms underlying OA remain only partially understood, hindering the development of targeted therapeutic strategies.

Methods: A transcriptome-wide association study (TWAS) was conducted for site-specific OA phenotypes using functional summary-based imputation (FUSION). High-confidence candidate genes were identified through rigorous quality control measures, including joint/conditional analysis, permutation tests, best model evaluation, and colocalization analysis. Co-expression network analysis was performed to elucidate the functional biology of these candidate genes. Druggable gene targets and their structural models were retrieved from the DrugBank and SWISS-MODEL databases. Finally, the enrichment of mitogen-activated protein kinase 3 (MAPK3) and SMAD3 in OA was validated biochemically using in vitro and in vivo OA models, as well as human histological sections.

Results: Utilizing the FUSION algorithm, TWAS identified 794 candidate genes for OA. After quality control, 14 genes were classified as high-confidence genes, with seven recognized as potential drug targets including GCAT, MAPK3, MST1R, PFKM, RAD9A, SMAD3, and USAP8. Co-expression analysis revealed a strong biological association between SMAD3 and MAPK3. Both in vitro and in vivo experiments demonstrated high activity and enriched expression of these two genes in OA.

Conclusion: The present study identified tissue-specific candidate genes and validated high-confidence druggable targets for OA, providing new insights into the genetic landscape and biological processes involved in OA. Further functional studies are warranted to confirm these findings.

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