Exploring antidiabetic drug targets as potential disease-modifying agents in osteoarthritisResearch in context
Kai Fu,
Shucheng Si,
Xinzhong Jin,
Yan Zhang,
Vicky Duong,
Qianying Cai,
Guangyi Li,
Win Min Oo,
Xianyou Zheng,
Cindy G. Boer,
Yuqing Zhang,
Xiaojuan Wei,
Changqing Zhang,
Youshui Gao,
David J. Hunter
Affiliations
Kai Fu
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Kolling Institute, Sydney Musculoskeletal Health, The University of Sydney, Sydney, Australia
Shucheng Si
Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China
Xinzhong Jin
Centre for Big Data Research in Health, University of New South Wales, Sydney, Australia
Yan Zhang
Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
Vicky Duong
Kolling Institute, Sydney Musculoskeletal Health, The University of Sydney, Sydney, Australia
Qianying Cai
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Guangyi Li
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Win Min Oo
Kolling Institute, Sydney Musculoskeletal Health, The University of Sydney, Sydney, Australia; Department of Physical Medicine and Rehabilitation, Mandalay General Hospital, University of Medicine Mandalay, Mandalay, Myanmar
Xianyou Zheng
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Cindy G. Boer
Department of Internal Medicine, Erasmus MC, Medical Center, Rotterdam, the Netherlands
Yuqing Zhang
Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA; The Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston, USA
Xiaojuan Wei
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Changqing Zhang
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding author.
Youshui Gao
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding author.
David J. Hunter
Kolling Institute, Sydney Musculoskeletal Health, The University of Sydney, Sydney, Australia
Summary: Background: Osteoarthritis is a leading cause of disability, and disease-modifying osteoarthritis drugs (DMOADs) could represent a pivotal advancement in treatment. Identifying the potential of antidiabetic medications as DMOADs could impact patient care significantly. Methods: We designed a comprehensive analysis pipeline involving two-sample Mendelian Randomization (MR) (genetic proxies for antidiabetic drug targets), summary-based MR (SMR) (for mRNA), and colocalisation (for drug-target genes) to assess their causal relationship with 12 osteoarthritis phenotypes. Summary statistics from the largest genome-wide association meta-analysis (GWAS) of osteoarthritis and gene expression data from the eQTLGen consortium were utilised. Findings: Seven out of eight major types of clinical antidiabetic medications were identified, resulting in fourteen potential drug targets. Sulfonylurea targets ABCC8/KCNJ11 were associated with increased osteoarthritis risk at any site (odds ratio (OR): 2.07, 95% confidence interval (CI): 1.50–2.84, P < 3 × 10−4), while PPARG, influenced by thiazolidinediones (TZDs), was associated with decreased risk of hand (OR: 0.61, 95% CI: 0.48–0.76, P < 3 × 10−4), finger (OR: 0.50, 95% CI: 0.35–0.73, P < 3 × 10−4), and thumb (OR: 0.49, 95% CI: 0.34–0.71, P < 3 × 10−4) osteoarthritis. Metformin and GLP1-RA, targeting GPD1 and GLP1R respectively, were associated with reduced risk of knee and finger osteoarthritis. In the SMR analyses, gene expression of KCNJ11, GANAB, ABCA1, and GSTP1, targeted by antidiabetic drugs, was significantly linked to at least one osteoarthritis phenotype and was replicated across at least two gene expression datasets. Additionally, increased KCNJ11 expression was related to decreased osteoarthritis risk and co-localised with at least one osteoarthritis phenotype. Interpretation: Our findings suggest a potential therapeutic role for antidiabetic drugs in treating osteoarthritis. The results indicate that certain antidiabetic drug targets may modify disease progression, with implications for developing targeted DMOADs. Funding: This study was funded by the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant (2022), the Shanghai Municipal Health Commission Health Industry Clinical Research Project (Grant No. 20224Y0139), Beijing Natural Science Foundation (Grant No. 7244458), and the Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation (Grant No. GZC20230130).
