Maresin 1 resolves aged-associated macrophage inflammation to improve bone regeneration.
Maresin 1 resolves aged-associated macrophage inflammation to improve bone regeneration.
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DOI：
10.1096/fj.202001145r
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Baht GS
中科院分区：
文献类型：
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作者：
Huang R;Vi L;Zong X;Baht GS
炎症与老年组织再生不良有关。具体来说，急性损伤后的长期炎症与老年患者骨折愈合减少和骨不愈合率增加有关。在这里，我们研究了使用Maresin 1 (MaR1)（一种omega-3脂肪酸衍生的促溶解剂）缓解胫骨骨折损伤后炎症并随后改善老年骨愈合的疗效。老龄小鼠（24月龄）接受胫骨骨折手术，并在伤后13天用载体或MaR1治疗。分别在伤后7天、14天、21天和28天采集骨折痂，观察炎症反应、软骨发育、骨沉积和机械完整性。经mar1处理的小鼠的愈合骨显示软骨形成减少，骨沉积增加，导致结构刚度增加，在修复后期骨折力增加。在早期阶段，MaR1治疗减少了骨折痂内促炎巨噬细胞的数量，降低了循环中炎症生物标志物的水平。在组织培养模型中，MaR1处理老年小鼠骨髓源性巨噬细胞保护细胞形成促炎表型并诱导抗炎命运。此外，经mar1处理的骨髓源性巨噬细胞分泌组被鉴定为成骨诱导，增强骨髓基质细胞成骨分化。我们的研究结果确定了炎症的消退，以及MaR1本身，是改善老年骨愈合的干预点。
Inflammaging is associated with poor tissue regeneration observed in advanced age. Specifically, protracted inflammation after acute injury has been associated with decreased bone fracture healing and increased rates of nonunion in elderly patients. Here, we investigated the efficacy of using Maresin 1 (MaR1), an omega-3 fatty acid-derived pro-resolving agent, to resolve inflammation after tibial fracture injury and subsequently improving aged bone healing. Aged (24-month-old mice) underwent tibial fracture surgery and were either treated with vehicle or MaR1 3 days after injury. Fracture calluses were harvested 7 days, 14 days, 21 days, and 28 days after injury to investigate inflammatory response, cartilage development, bone deposition, and mechanical integrity, respectively. Healing bones from MaR1-treated mice displayed decreased cartilage formation and increased bone deposition which resulted in increased structural stiffness and increased force to fracture in the later stages of repair. In the early stages, MaR1 treatment decreased the number of pro-inflammatory macrophages within the fracture callus and decreased the level of inflammatory biomarkers in circulation. In tissue culture models, MaR1 treatment of bone marrow-derived macrophages from aged mice protected cells form a pro-inflammatory phenotype and induced an anti-inflammatory fate. Furthermore, the secretome of MaR1-treated bone marrow-derived macrophages was identified as osteoinductive, enhancing osteoblast differentiation of bone marrow stromal cells. Our findings here identify resolution of inflammation, and MaR1 itself, to be a point of intervention to improve aged bone healing.