Hypoxia-Mimicking Mediated Macrophage-Elimination of Erythrocytes Promotes Bone Regeneration via Regulating Integrin α v β 3 /Fe ²⁺ -Glycolysis-Inflammation.

Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE

Original Publication: Weinheim : WILEY-VCH, [2014]-

Bone Regeneration*/drug effects ; Erythrocytes*/metabolism ; Erythrocytes*/drug effects ; Macrophages*/metabolism ; Macrophages*/drug effects ; Integrin alphaVbeta3*/metabolism ; Inflammation*/metabolism; Animals ; Mice ; Hypoxia/metabolism ; Iron/metabolism

Erythrocytes are the dominant component of a blood clot in terms of volume and number. However, longstanding compacted erythrocytes in blood clots form a physical barrier and make fibrin mesh more anti-fibrinolytic, thus impeding infiltration of mesenchymal stem cells. The necrosis or lysis of erythrocytes that are not removed timely can also lead to the release of pro-inflammatory toxic metabolites, interfering with bone regeneration. Proper bio-elimination of erythrocytes is essential for an undisturbed bone regeneration process. Here, hypoxia-mimicking is applied to enhance macrophage-elimination of erythrocytes. The effect of macrophage-elimination of erythrocytes on the macrophage intracellular reaction, bone regenerative microenvironment, and bone regeneration outcome is investigated. Results show that the hypoxia-mimicking agent dimethyloxalylglycine successfully enhances erythrophagocytosis by macrophages in a dose-dependent manner primarily by up-regulating the expression of integrin α v β 3 . Increased phagocytosed erythrocytes then regulate macrophage intracellular Fe ²⁺ -glycolysis-inflammation, creating an improved bone regenerative microenvironment characterized by loose fibrin meshes with down-regulated local inflammatory responses in vivo, thus effectively promoting early osteogenesis and ultimate bone generation. Modulating macrophage-elimination of erythrocytes can be a promising strategy for eradicating erythrocyte-caused bone regeneration hindrance and offers a new direction for advanced biomaterial development focusing on the bio-elimination of erythrocytes.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

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82301122 National Natural Science Foundation of China; 82071167 National Natural Science Foundation of China; 2023A0505050138 Science and Technology Program of Guangdong, China; 2023B03J1232 Science and Technology Program of Guangzhou, China; 2024A04J4853 Science and Technology Program of Guangzhou, China; 2022YFA1104400 Key Technologies Research and Development Program

Keywords: bone regeneration; erythrocyte clearance; hypoxia‐mimicking; inflammatory responses; macrophage phagocytosis

0 (Integrin alphaVbeta3)
E1UOL152H7 (Iron)

Date Created: 20241001 Date Completed: 20241204 Latest Revision: 20241207

20250114

PMC11615788

10.1002/advs.202403921

39352318