Matrix stiffness regulates bone repair by modulating 12-lipoxygenase-mediated early inflammation.

Abstract

Lipid metabolism in macrophages has been increasingly emphasized in exerting an anti-inflammatory effect and accelerating fracture healing. 12-lipoxygenase (12-LOX) is expressed in several cell types, including macrophages, and oxidizes polyunsaturated fatty acids (PUFAs) to generate both pro- and anti-inflammatory lipid mediators, of which the n-3 PUFAs play an important part in tissue homeostasis/fibrosis. Although mechanical factor regulates the lipid metabolic axis of inflammatory cells, specifically matrix stiffness influences macrophages metabolic responses, little is known about how matrix stiffness affects the 12-LOX-mediated early inflammation in bone repair. In the present study, demineralized bone matrix (DBM) scaffolds with different matrix stiffness were constructed by controlling the duration of decalcification (0 h (control), 1 h (high), 12 h (medium), and 5 d (low)) to repair the defected rat skull. The expression of inflammatory cytokines and macrophages polarization were analyzed. The lipid metabolites and lipid mediators' biosynthesis by matrix stiffness-regulated were further detected. The results showed that the low matrix stiffness could polarize macrophages into an anti-inflammatory phenotype, promote the expression of anti-inflammatory cytokines and specialized pro-resolving lipid mediators (SPMs) biosynthesis beneficial for the osteogenesis of mesenchymal stem cells (MSCs). After treated with ML355, the expression of anti-inflammatory cytokines/proteins and SPMs biosynthesis in macrophages cultured on low-matrix stiffness scaffolds were repressed, and there were almost no statistical differences among all groups. Findings from this study support that matrix stiffness regulates bone repair by modulating 12-LOX-mediated early inflammation, which suggest a direct mechanical impact of matrix stiffness on macrophages lipid metabolism and provide a new insight into the clinical application of SPMs for bone regeneration.

• Authors: Dongdong Yao, Fangyu Qiao, Chenchen Song, Yonggang Lv
• Journal: Materials science & engineering. C, Materials for biological applications (Mater Sci Eng C Mater Biol Appl) Vol. 128 Pg. 112359 (Sep 2021) ISSN: 1873-0191 [Electronic] Netherlands
• PMID: 34474906 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Arachidonate 12-Lipoxygenase

Topics

• Animals
• Arachidonate 12-Lipoxygenase
• Bone Regeneration
• Inflammation
• Mesenchymal Stem Cells
• Osteogenesis
• Rats