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

Yuanjing Ding, Jianlu Wei, Aubryanna Hettinghouse, Guangfei Li, Xin Li, Thomas A. Einhorn, Chuan ju Liu

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)77-89
Number of pages13
JournalAnnals of the New York Academy of Sciences
Issue number1
StatePublished - Feb 18 2021


  • TNF-α
  • impaired fracture healing
  • progranulin
  • tumor necrosis factor receptors
  • type 2 diabetes

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • History and Philosophy of Science


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