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.

中文翻译：

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前颗粒蛋白可通过TNFR途径促进2型糖尿病小鼠的骨折愈合

2型糖尿病（T2DM）会显着增加骨骼脆性和骨折风险。前颗粒蛋白（PGRN）在生理和1型糖尿病情况下均能促进骨折愈合。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。钻孔，Bonnarens和Einhorn模型用于研究PGRN在体内T2DM骨折愈合中的作用。分离了原代骨髓细胞用于分子和信号研究，并进行了逆转录聚合酶链反应，免疫组化染色和蛋白质印迹以评估体外PGRN的作用。PGRN mRNA和蛋白表达在T2DM模型中上调。重组PGRN的局部给药有效促进了T2DM骨折的体内愈合。另外，PGRN可能通过TNFR2-Akt和Erk1 / 2途径在软骨内骨化过程中诱导同化代谢。此外，PGRN在T2DM骨再生过程中显示出抗炎活性。这些发现表明，局部施用外源性PGRN可能是支持T2DM患者骨再生的另一种策略。此外，PGRN可能具有治疗其他与TNFR相关的代谢性疾病的潜力。