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颗粒蛋白前体通过 TNFR 通路促进 2 型糖尿病小鼠骨折愈合。

Progranulin promotes bone fracture healing via TNFR pathways in mice with type 2 diabetes mellitus.

机构信息

Department of Orthopaedic Surgery, New York University Medical Center, New York, New York.

Department of Orthopaedic Surgery, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

出版信息

Ann N Y Acad Sci. 2021 Apr;1490(1):77-89. doi: 10.1111/nyas.14568. Epub 2021 Feb 4.

DOI:10.1111/nyas.14568
PMID:33543485
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8138780/
Abstract

Type 2 diabetes mellitus (T2DM) significantly increases bone fragility and fracture risk. Progranulin (PGRN) promotes bone fracture healing in both physiological and type 1 diabetic conditions. The present study aimed to investigate the role of PGRN in T2DM bone fracture healing. MKR mice (with an FVB/N genetic background) were used as the T2DM model. Drill-hole and Bonnarens and Einhorn models were used to investigate the role of PGRN in T2DM fracture healing in vivo. Primary bone marrow cells were isolated for molecular and signaling studies, and reverse transcription-polymerase chain reaction, immunohistochemical staining, and western blotting were performed to assess PGRN effects in vitro. PGRN mRNA and protein expression were upregulated in the T2DM model. Local administration of recombinant PGRN effectively promoted T2DM bone fracture healing in vivo. Additionally, PGRN could induce anabolic metabolism during endochondral ossification through the TNFR2-Akt and Erk1/2 pathways. Furthermore, PGRN showed anti-inflammatory activity in the T2DM bone regeneration process. These findings suggest that local administration of exogenous PGRN may be an alternative strategy to support bone regeneration in patients with T2DM. Additionally, PGRN might hold therapeutic potential for other TNFR-related metabolic disorders.

摘要

2 型糖尿病（T2DM）显著增加了骨脆性和骨折风险。颗粒蛋白前体（PGRN）可促进生理和 1 型糖尿病条件下的骨骨折愈合。本研究旨在探讨 PGRN 在 T2DM 骨折愈合中的作用。MKR 小鼠（具有 FVB/N 遗传背景）被用作 T2DM 模型。使用钻孔和 Bonnarens 和 Einhorn 模型来研究 PGRN 在体内 T2DM 骨折愈合中的作用。分离原代骨髓细胞进行分子和信号研究，并进行逆转录-聚合酶链反应、免疫组织化学染色和 Western blot 分析，以评估 PGRN 在体外的作用。PGRN mRNA 和蛋白表达在 T2DM 模型中上调。局部给予重组 PGRN 可有效促进体内 T2DM 骨折愈合。此外，PGRN 可通过 TNFR2-Akt 和 Erk1/2 通路诱导骺板内骨化过程中的合成代谢。此外，PGRN 在 T2DM 骨再生过程中具有抗炎活性。这些发现表明，局部给予外源性 PGRN 可能是支持 T2DM 患者骨再生的一种替代策略。此外，PGRN 可能对其他与 TNFR 相关的代谢紊乱具有治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c254/8138780/a23a8c597d09/nihms-1699489-f0006.jpg
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