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

doi:10.1111/nyas.14568

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

Molecular Pathobiology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	77-89
Number of pages	13
Journal	Annals of the New York Academy of Sciences
Volume	1490
Issue number	1
DOIs	https://doi.org/10.1111/nyas.14568
State	Published - Feb 18 2021

Keywords

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

ASJC Scopus subject areas

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

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10.1111/nyas.14568

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title = "Progranulin promotes bone fracture healing via TNFR pathways in mice with type 2 diabetes mellitus",

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.",

keywords = "TNF-α, impaired fracture healing, progranulin, tumor necrosis factor receptors, type 2 diabetes",

author = "Yuanjing Ding and Jianlu Wei and Aubryanna Hettinghouse and Guangfei Li and Xin Li and Einhorn, {Thomas A.} and Liu, {Chuan ju}",

note = "Funding Information: This work was supported by the National Institutes of Health (Grants R01AR076900, R01AR062207, R01AR061484, and 1R01NS103931) and a U.S. Department of Defense research Grant (W81XWH-16-1-0482 to C.-J.L.). Publisher Copyright: {\textcopyright} 2021 New York Academy of Sciences.",

year = "2021",

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doi = "10.1111/nyas.14568",

language = "English (US)",

volume = "1490",

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T1 - Progranulin promotes bone fracture healing via TNFR pathways in mice with type 2 diabetes mellitus

AU - Ding, Yuanjing

AU - Wei, Jianlu

AU - Hettinghouse, Aubryanna

AU - Li, Guangfei

AU - Li, Xin

AU - Einhorn, Thomas A.

AU - Liu, Chuan ju

N1 - Funding Information: This work was supported by the National Institutes of Health (Grants R01AR076900, R01AR062207, R01AR061484, and 1R01NS103931) and a U.S. Department of Defense research Grant (W81XWH-16-1-0482 to C.-J.L.). Publisher Copyright: © 2021 New York Academy of Sciences.

PY - 2021/2/18

Y1 - 2021/2/18

N2 - 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.

AB - 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.

KW - TNF-α

KW - impaired fracture healing

KW - progranulin

KW - tumor necrosis factor receptors

KW - type 2 diabetes

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JO - Annals of the New York Academy of Sciences

JF - Annals of the New York Academy of Sciences

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

Abstract

Keywords

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