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World J Diabetes. Nov 15, 2026; 17(11): 124042
Published online Nov 15, 2026. doi: 10.4239/wjd.124042
Published online Nov 15, 2026. doi: 10.4239/wjd.124042
Ganagliflozin proline attenuates osteogenic dysfunction and inflammatory signaling during exposure to advanced glycation end products in murine osteoblasts
Zhi-Peng Li, Dong Li, Peng Wang, Chang-Jiang Zhang, Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Zhi-Peng Li, Chang-Jiang Zhang, Tianjian Advanced Biomedical Laboratory, Zhengzhou University, Zhengzhou 450001, Henan Province, China
Zhi-Peng Li, Dong Li, Peng Wang, Chang-Jiang Zhang, Henan Provincial Key Discipline of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Han Li, Department of Orthopedics, Affiliated Dongyang Hospital of Wenzhou Medical University, Jinhua 322100, Zhejiang Province, China
Jia-Li Xu, Dong-Juan He, Department of Endocrinology, The Second People’s Hospital of Quzhou, Quzhou 324000, Zhejiang Province, China
Ya-Jing Liu, School of Mechanics and Safety Engineering, Zhengzhou University, Zhengzhou 450001, Henan Province, China
Lei Xiang, Department of Rehabilitation Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Shi-Yu Xu, Cheng-Zheng Duan, Sheng-Xin Wang, Cheng Luo, Department of Endocrinology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou 324000, Zhejiang Province, China
Jin-Ke Sun, Third Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Co-first authors: Zhi-Peng Li and Han Li.
Co-corresponding authors: Dong-Juan He and Cheng Luo.
Author contributions: Li ZP conceived and designed the study, established the overall experimental framework, performed the main cellular and molecular experiments, analyzed and interpreted the data, prepared the figures, and drafted the manuscript; Li H contributed to experimental implementation, cell culture, pharmacological intervention assays, data collection, statistical analysis, and manuscript revision; Xu JL contributed to the interpretation of endocrine and metabolic mechanisms, organization of advanced glycation end products-related experimental information, literature analysis, and manuscript editing; Liu YJ contributed to methodological discussion, molecular docking-related analysis, data visualization, figure refinement, and manuscript revision; Li D contributed to cell-based experiments, Western blotting-related data collection, and interpretation of osteogenesis-related results; Wang P contributed to quantitative polymerase chain reaction related data analysis, figure organization, statistical verification, and manuscript editing; Xiang L contributed to interpretation of osteoblast functional recovery, rehabilitation-related academic discussion, and critical revision of the manuscript; Xu SY contributed to literature collection, organization of sodium-glucose cotransporter 2 inhibitor-related evidence, data checking, and manuscript revision; Duan CZ contributed to endocrine-related academic discussion, interpretation of advanced glycation end products/receptor for advanced glycation end products/nuclear factor kappa B signaling, and critical revision of the manuscript; Wang SX contributed to data organization, reference checking, Supplementary material preparation, and manuscript editing; Sun JK contributed to orthopedic interpretation, discussion of bone metabolism and osteogenic differentiation, and manuscript revision; Zhang CJ contributed to study discussion, interpretation of collagen- and bone matrix-related findings, and manuscript revision; He DJ supervised the study, contributed to study design, project administration, and clinical relevance interpretation, provided academic guidance, and critically revised the manuscript for important intellectual content; Luo C supervised the study, contributed to conceptualization, project coordination, mechanistic interpretation, and critical revision of the manuscript, and approved the final version for publication; Li ZP and Li H contributed equally to this work and share first authorship; He DJ and Luo C contributed equally to this work and share correspondence; all authors made a significant contribution to the work reported, including conception, study design, experimental execution, data acquisition, analysis and interpretation, or manuscript preparation and revision; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work.
AI contribution statement: During manuscript revision, the authors used ChatGPT (OpenAI, GPT-5) to assist with English-language editing, structural organization, and consistency checking. The tool was not used to generate experimental data or images or to make independent statistical or scientific decisions. All AI-assisted content was reviewed and verified by the authors, who take full responsibility for the final manuscript.
Supported by the Zhejiang Medical Association Clinical Medical Research Special Fund Project, “Mechanistic study and clinical efficacy observation of SGLT-2 inhibitors in improving type 2 diabetic bone fragility by regulating the AGEs-COL1 axis”, No. 2025ZYC-Z32; Henan Provincial Key Research and Development Program, No. 231111311000; Henan Provincial Higher Education Institutions Key Research Project, No. 26A320038; Henan Provincial Science and Technology Project, No. 262102310123; and Henan Provincial Medical Science and Technology Key Project, No. LHGJ20250403, No. LHGJ20220566 and No. LHGJ20240365.
Institutional review board statement: The study protocol was reviewed and approved for ethics exemption and record filing by the Medical Ethics Committee of the Fifth Affiliated Hospital of Zhengzhou University (approval No. YJ-D-2026022). The study did not involve human participants, human-derived specimens, identifiable personal information, or clinical data.
Institutional animal care and use committee statement: The animal-study protocol associated with this research project was reviewed and approved by the Medical Ethics Committee of the Fifth Affiliated Hospital of Zhengzhou University (approval No. YJ-D-2026022). The present manuscript reports only experiments using the established MC3T3-E1 mouse preosteoblast cell line and a cell-free system; no live-animal experiments or animal-derived data are reported.
Conflict-of-interest statement: The Ganagliflozin Proline study material was provided by Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd and Jilin Huikang Pharmaceutical Co., Ltd. Neither company had a role in study design, data collection, data analysis, data interpretation, manuscript preparation, or the decision to submit the article for publication. The authors declare no other conflicts of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: All data supporting the findings of this study are included in the article and its Supplementary material. Full uncropped original Western blot images corresponding to Figures 4, 5 and 6 are provided in the Supplementary material. Additional source data and statistical outputs are available from the corresponding author, Cheng Luo (luochengmi805@wmu.edu.cn), upon reasonable request.
Corresponding author: Cheng Luo, MD, Chief Physician, Department of Endocrinology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, No. 100 Minjiang Avenue, Kecheng District, Quzhou 324000, Zhejiang Province, China. luochengmi805@wmu.edu.cn
Received: June 4, 2026
Revised: August 14, 2026
Accepted: October 23, 2026
Published online: November 15, 2026
Processing time: 154 Days and 10.5 Hours
Revised: August 14, 2026
Accepted: October 23, 2026
Published online: November 15, 2026
Processing time: 154 Days and 10.5 Hours
Core Tip
Core Tip: This study demonstrates that ganagliflozin proline (Gana Pro) protects MC3T3-E1 osteoblasts against advanced glycation end product-induced dysfunction. Gana Pro improved proliferation, collagen I expression, osteogenic-marker expression, alkaline phosphatase activity, calcium deposition, and matrix mineralization. These benefits were accompanied by lower receptor for advanced glycation end products (RAGE) expression, p65 phosphorylation, and tumor necrosis factor alpha expression. A separate RAGE-knockdown/phorbol 12-myristate 13-acetate experiment supported the functional involvement of this signaling axis in advanced glycation end products-induced osteogenic suppression. The combined evidence identifies RAGE/nuclear factor kappa B signaling as a plausible mechanistic contributor, although drug-specific pathway mediation requires direct rescue validation.