Progranulin promotes diabetic fracture healing in mice with type 1 diabetes

Jianlu Wei, Lei Zhang, Yuanjing Ding, Ronghan Liu, Yuqi Guo, Aubryanna Hettinghouse, John Buza, Jean De La Croix, Xin Li, Thomas A. Einhorn, Chuan Ju Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor-alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor-like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN-binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti-inflammatory signaling pathways are involved in PGRN-stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.

Original languageEnglish (US)
Pages (from-to)43-56
Number of pages14
JournalAnnals of the New York Academy of Sciences
Volume1460
Issue number1
DOIs
StatePublished - Jan 1 2020

Keywords

  • TNFR1
  • TNFR2
  • impaired fracture healing
  • progranulin
  • type 1 diabetes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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