Progranulin Promotes Bone Fracture Healing Via TNFR Pathways in Mice with Type 2 Diabetes Mellitus

Overview

Journal Ann N Y Acad Sci

Specialty Science

Date 2021 Feb 5

PMID 33543485

Citations 13

Authors

Yuanjing Ding

Jianlu Wei

Aubryanna Hettinghouse

Guangfei Li

Xin Li

Thomas A Einhorn

Chuan-Ju Liu

Affiliations

Soon will be listed here.

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.

Citing Articles

Progranulin Protects Against Osteoporosis by Regulating Osteoclast and Osteoblast Balance via TNFR Pathway.

Wang S, Zhang H, Zhu Y, Zhou X, Zhai H, He Q J Cell Mol Med. 2025; 29(3):e70385.

PMID: 39910695 PMC: 11798871. DOI: 10.1111/jcmm.70385.

Progranulin deficiency associates with postmenopausal osteoporosis via increasing ubiquitination of estrogen receptor α.

Li G, Wang A, Tang W, Fu W, Tian Q, Jian J Genes Dis. 2024; 12(1):101221.

PMID: 39559258 PMC: 11570241. DOI: 10.1016/j.gendis.2024.101221.

Advantages and Limitations of Diabetic Bone Healing in Mouse Models: A Narrative Review.

Maisenbacher T, Ehnert S, Histing T, Nussler A, Menger M Biomedicines. 2023; 11(12).

PMID: 38137522 PMC: 10741210. DOI: 10.3390/biomedicines11123302.

Atsttrin regulates osteoblastogenesis and osteoclastogenesis through the TNFR pathway.

Liu K, Wang Z, Liu J, Zhao W, Qiao F, He Q Commun Biol. 2023; 6(1):1251.

PMID: 38081906 PMC: 10713527. DOI: 10.1038/s42003-023-05635-y.

Progranulinopathy: A diverse realm of disorders linked to progranulin imbalances.

Huang G, Jian J, Liu C Cytokine Growth Factor Rev. 2023; 76:142-159.

PMID: 37981505 PMC: 10978308. DOI: 10.1016/j.cytogfr.2023.11.001.

References

Alquezar C, de la Encarnacion A, Moreno F, de Munain A, Martin-Requero A . Progranulin deficiency induces overactivation of WNT5A expression via TNF-α/NF-κB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers. J Psychiatry Neurosci. 2015; 41(4):225-39. PMC: 4915932. DOI: 10.1503/jpn.150131. View

Pearson-Stuttard J, Blundell S, Harris T, Cook D, Critchley J . Diabetes and infection: assessing the association with glycaemic control in population-based studies. Lancet Diabetes Endocrinol. 2015; 4(2):148-58. DOI: 10.1016/S2213-8587(15)00379-4. View

Li H, Zhang Z, Feng D, Xu L, Li F, Liu J . PGRN exerts inflammatory effects via SIRT1-NF-κB in adipose insulin resistance. J Mol Endocrinol. 2020; 64(3):181-193. DOI: 10.1530/JME-19-0211. View

Feng J, Guo F, Jiang B, Zhang Y, Frenkel S, Wang D . Granulin epithelin precursor: a bone morphogenic protein 2-inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis. FASEB J. 2010; 24(6):1879-92. PMC: 2874481. DOI: 10.1096/fj.09-144659. View

Hotamisligil G . The role of TNFalpha and TNF receptors in obesity and insulin resistance. J Intern Med. 1999; 245(6):621-5. DOI: 10.1046/j.1365-2796.1999.00490.x. View

Wei J, Hettinghouse A, Liu C . The role of progranulin in arthritis. Ann N Y Acad Sci. 2016; 1383(1):5-20. DOI: 10.1111/nyas.13191. View

Compston J . Type 2 diabetes mellitus and bone. J Intern Med. 2017; 283(2):140-153. DOI: 10.1111/joim.12725. View

Zhao Y, Liu B, Tian Q, Wei J, Richbourgh B, Liu C . Progranulin protects against osteoarthritis through interacting with TNF-α and β-Catenin signalling. Ann Rheum Dis. 2014; 74(12):2244-2253. PMC: 4408266. DOI: 10.1136/annrheumdis-2014-205779. View

Samelson E, Demissie S, Cupples L, Zhang X, Xu H, Liu C . Diabetes and Deficits in Cortical Bone Density, Microarchitecture, and Bone Size: Framingham HR-pQCT Study. J Bone Miner Res. 2017; 33(1):54-62. PMC: 5771832. DOI: 10.1002/jbmr.3240. View

10.

Kayal R, Siqueira M, Alblowi J, McLean J, Krothapalli N, Faibish D . TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1. J Bone Miner Res. 2010; 25(7):1604-15. PMC: 3154002. DOI: 10.1002/jbmr.59. View

11.

Jian J, Li G, Hettinghouse A, Liu C . Progranulin: A key player in autoimmune diseases. Cytokine. 2016; 101:48-55. PMC: 5303690. DOI: 10.1016/j.cyto.2016.08.007. View

12.

Liu C . Progranulin: a promising therapeutic target for rheumatoid arthritis. FEBS Lett. 2011; 585(23):3675-80. PMC: 3162080. DOI: 10.1016/j.febslet.2011.04.065. View

13.

Albeltagy E, Hammour A, Albeltagy S . Potential value of serum Progranulin as a biomarker for the presence and severity of micro vascular complications among Egyptian patients with type 2 diabetes mellitus. J Diabetes Metab Disord. 2019; 18(1):217-228. PMC: 6582124. DOI: 10.1007/s40200-019-00406-1. View

14.

Wei J, Fu W, Hettinghouse A, He W, Lipson K, Liu C . Role of ADAMTS-12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor. Arthritis Rheumatol. 2018; 70(11):1745-1756. PMC: 6203634. DOI: 10.1002/art.40552. View

15.

Youn B, Bang S, Kloting N, Park J, Lee N, Oh J . Serum progranulin concentrations may be associated with macrophage infiltration into omental adipose tissue. Diabetes. 2008; 58(3):627-36. PMC: 2646061. DOI: 10.2337/db08-1147. View

16.

Lekkala S, Taylor E, Hunt H, Donnelly E . Effects of Diabetes on Bone Material Properties. Curr Osteoporos Rep. 2019; 17(6):455-464. PMC: 6986388. DOI: 10.1007/s11914-019-00538-6. View

17.

Lai Y, Bai X, Zhao Y, Tian Q, Liu B, Lin E . ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis. Ann Rheum Dis. 2013; 73(8):1575-84. PMC: 4418017. DOI: 10.1136/annrheumdis-2013-203561. View

18.

Fasshauer M, Bluher M, Stumvoll M . Adipokines in gestational diabetes. Lancet Diabetes Endocrinol. 2014; 2(6):488-99. DOI: 10.1016/S2213-8587(13)70176-1. View

19.

Kayal R, Tsatsas D, Bauer M, Allen B, Al-Sebaei M, Kakar S . Diminished bone formation during diabetic fracture healing is related to the premature resorption of cartilage associated with increased osteoclast activity. J Bone Miner Res. 2007; 22(4):560-8. PMC: 3109431. DOI: 10.1359/jbmr.070115. View

20.

Qu H, Deng H, Hu Z . Plasma progranulin concentrations are increased in patients with type 2 diabetes and obesity and correlated with insulin resistance. Mediators Inflamm. 2013; 2013:360190. PMC: 3588183. DOI: 10.1155/2013/360190. View