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Progranulin promotes diabetic fracture healing in mice with type 1 diabetes
Author(s) -
Wei Jianlu,
Zhang Lei,
Ding Yuanjing,
Liu Ronghan,
Guo Yuqi,
Hettinghouse Aubryanna,
Buza John,
De La Croix Jean,
Li Xin,
Einhorn Thomas A.,
Liu Chuanju
Publication year - 2020
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.14208
Subject(s) - type 2 diabetes , diabetes mellitus , bone healing , chemistry , medicine , endocrinology , microbiology and biotechnology , biology , surgery
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.