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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 finding

Jialin Song,1,2 Xueyang Li,3 Yingli Li,4,5 Junyi Che,6 Xiaoming Li,6 Xiaotian Zhao,6 Yinghui Chen,7,* Xianyou Zheng,1,* Weien Yuan6,* 1Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 2Department of Orthopedics, Shanghai University of Medicine and Health, Shanghai, Sixth People’s Hospital East Campus, Shanghai, 3Department of Plastic and Reconstructive Surgery, Xuzhou Medical College Affiliated Hospital, Xuzhou, Jiangsu, 4Department of Plastic Surgery, The General Hospital of Jinan Military Command, Jinan, Shandong, 5Department of Plastic Surgery, Chang Hai Hospital, Second Military Medical University, 6School of Pharmacy, Shanghai Jiao Tong University, 7Department of Neurology, Jinshan Hospital, Fudan University, JinShan District, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: MicroRNA (miRNA) has great potential to treat a wide range of illnesses by regulating the expression of eukaryotic genes. Biomaterials with high transfection efficiency and low toxicity are needed to deliver miRNA to target cells. In this study, a biodegradable and biocompatible cationic polymer (PDAPEI) was synthetized from low molecular weight polyethyleneimine (PEI1.8kDa) cross-linked with 2,6-pyridinedicarboxaldehyde. PDAPEI showed a lower cytotoxicity and higher transfection efficiency than PEI25kDa in transfecting miR-221/222 into rat Schwann cells (SCs). The upregulation of miR-221/222 in SCs promoted the expression of nerve growth factor and myelin basic protein in vitro. The mouse sciatic nerve crush injury model was used to evaluate the effectiveness of PDAPEI/miR-221/222 complexes for nerve regeneration in vivo. The results of electrophysiological tests, functional assessments, and histological and immunohistochemistry analyses demonstrated that PDAPEI/miR-221/222 complexes significantly promoted nerve regeneration after sciatic nerve crush, specificall

Jialin Song,1,2 Xueyang Li,3 Yingli Li,4,5 Junyi Che,6 Xiaoming Li,6 Xiaotian Zhao,6 Yinghui Chen,7,* Xianyou Zheng,1,* Weien Yuan6,* 1Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 2Department of Orthopedics, Shanghai University of Medicine and Health, Shanghai, Sixth People’s Hospital East Campus, Shanghai, 3Department of Plastic and Reconstructive Surgery, Xuzhou Medical College Affiliated Hospital, Xuzhou, Jiangsu, 4Department of Plastic Surgery, The General Hospital of Jinan Military Command, Jinan, Shandong, 5Department of Plastic Surgery, Chang Hai Hospital, Second Military Medical University, 6School of Pharmacy, Shanghai Jiao Tong University, 7Department of Neurology, Jinshan Hospital, Fudan University, JinShan District, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: MicroRNA (miRNA) has great potential to treat a wide range of illnesses by regulating the expression of eukaryotic genes. Biomaterials with high transfection efficiency and low toxicity are needed to deliver miRNA to target cells. In this study, a biodegradable and biocompatible cationic polymer (PDAPEI) was synthetized from low molecular weight polyethyleneimine (PEI1.8kDa) cross-linked with 2,6-pyridinedicarboxaldehyde. PDAPEI showed a lower cytotoxicity and higher transfection efficiency than PEI25kDa in transfecting miR-221/222 into rat Schwann cells (SCs). The upregulation of miR-221/222 in SCs promoted the expression of nerve growth factor and myelin basic protein in vitro. The mouse sciatic nerve crush injury model was used to evaluate the effectiveness of PDAPEI/miR-221/222 complexes for nerve regeneration in vivo. The results of electrophysiological tests, functional assessments, and histological and immunohistochemistry analyses demonstrated that PDAPEI/miR-221/222 complexes significantly promoted nerve regeneration after sciatic nerve crush, specificall