Progranulin promotes bone fracture healing via TNFR pathways in mice with type 2 diabetes mellitus.
Progranulin promotes bone fracture healing via TNFR pathways in mice with type 2 diabetes mellitus.
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颗粒体蛋白前体通过 TNFR 途径促进 2 型糖尿病小鼠骨折愈合。
DOI：
10.1111/nyas.14568
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发表时间：
2021-04
影响因子：
5.2
通讯作者：
Liu CJ
中科院分区：
文献类型：
--
作者：
Ding Y;Wei J;Hettinghouse A;Li G;Li X;Einhorn TA;Liu CJ
2型糖尿病(T2 DM)显著增加骨脆性和骨折风险。原颗粒蛋白(PGRN)在生理性和1型糖尿病条件下都能促进骨折愈合。本研究旨在探讨PGRN在T2 DM骨折愈合中的作用。以具有FVB遗传背景的MKR小鼠作为T2 DM模型。建立钻孔模型、Bonnarens模型和Einhorn模型，研究PGRN在体内T2 DM骨折愈合中的作用。分离原代骨髓细胞进行分子和信号转导研究，采用逆转录聚合酶链式反应、免疫组织化学染色和Western blotting等方法评价PGRN的体外作用。T2 DM患者PGRN基因和蛋白表达上调。体内局部应用重组PGRN可有效促进T2 DM骨折愈合。此外，PGRN还可通过TNFR2-Akt和ERK1/2途径诱导软骨内成骨过程中的合成代谢。此外，PGRN在T2 DM骨再生过程中具有抗炎活性。这些发现表明，局部应用外源性PGRN可能是支持T2 DM患者骨再生的一种替代策略。此外，PGRN还可能具有治疗其他TNFR相关代谢疾病的潜力。
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 (with FVB genetic background) mice were used as T2DM model. Drill-hole and Bonnarens and Einhorn models were established 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 transcriptase-polymerase chain reaction, immunohistochemical staining, and western blotting were performed to assess PGRN effects in vitro. PGRN mRNA and protein expression were upregulated in T2DM. Local administration of recombinant PGRN effectively promoted T2DM bone fracture healing in vivo. Additionally, PGRN could induce anabolic metabolism during endochondral ossification through 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 represent an alternative strategy to support bone regeneration in patients with T2DM. Additionally, PGRN might also hold therapeutic potential for other TNFR-related metabolic disorders.
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促生蛋白：一种生长因子，一种新型的TNFR配体和药物靶标。
影响因子：
13.5
作者：
Liu, Chuan-ju;Bosch, Xavier
通讯作者：
Bosch, Xavier
影响因子：
4.8
作者：
Fu, Wenyu;Hu, Wenhuo;Liu, Chuan-ju
通讯作者：
Liu, Chuan-ju
影响因子：
3.5
作者：
Liu CJ
通讯作者：
Liu CJ
影响因子：
6.2
作者：
Kayal, Rayyan A.;Siqueira, Michelle;Alblowi, Jazia;McLean, Jody;Krothapalli, Nanarao;Faibish, Dan;Einhorn, Thomas A.;Gerstenfeld, Louis C.;Graves, Dana T.
通讯作者：
Graves, Dana T.
影响因子：
4.1
作者：
Lim JC;Ko KI;Mattos M;Fang M;Zhang C;Feinberg D;Sindi H;Li S;Alblowi J;Kayal RA;Einhorn TA;Gerstenfeld LC;Graves DT
通讯作者：
Graves DT