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Macrophage GIT1 Contributes to Bone Regeneration by Regulating Inflammatory Responses in an ERK / NRF2 ‐Dependent Way
Author(s) -
Zhao ShuJie,
Liu Hao,
Chen Jian,
Qian DingFei,
Kong FanQi,
Jie Jian,
Yin GuoYong,
Li QingQing,
Fan Jin
Publication year - 2020
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.4099
Subject(s) - mapk/erk pathway , macrophage , biology , microbiology and biotechnology , inflammation , kinase , cancer research , immunology , in vitro , biochemistry
Despite the best treatment, approximately 10% of fractures still face undesirable repair. Recently, many studies have focused on the importance of macrophages in bone repair; however, the cellular mechanisms by which they work are not yet fully understood. In this study, we explored the functions of macrophage G‐protein‐coupled receptor interacting protein 1 (GIT1) in healing a tibial monocortical defect model. Using GIT1 flox/flox Lyz2‐Cre (GIT1 CKO) mice, we observed that a GIT1 deficiency in the macrophages led to an exacerbation of interleukin 1β (IL1β) production, more M1‐like macrophage infiltration, and impaired intramembranous ossification in vivo. The results of in vitro assays further indicated that the macrophage GIT1 plays a critical role in several cellular processes in response to lipopolysaccharide (LPS), such as anti‐oxidation, IL1β production alleviation, and glycolysis control. Although GIT1 has been recognized as a scaffold protein, our data clarified that GIT1‐mediated extracellular‐signal‐regulated kinase (ERK) phosphorylation could activate nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) in macrophages after LPS treatment. Moreover, we demonstrated that macrophage GIT1‐activated ERK/NRF2 negatively regulates the 6‐phosphofructo‐2‐kinase/fructose‐2, 6‐biphosphatase 3 (PFKFB3), facilitating the decrease of glycolysis. Our findings uncovered a previously unrecognized role of GIT1 in regulating ERK/NRF2 in macrophages to control the inflammatory response, suggesting that macrophage GIT1 could be a potential target to improve bone regeneration. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..