Correction of Immune Response Improves Aged Fracture Healing

摘要 骨折发生在50%的人口造成显着的发病率和死亡率和成本 每年超过200亿美元的医疗保健。骨折修复是一个复杂的过程， 信号分子和细胞过程，所有这些都还没有完全确定。因素，如先进的 年龄，可能会对这一过程产生负面影响，从而损害恢复和适当的骨愈合。我们的初步数据 表明巨噬细胞被募集到幼鼠骨损伤部位创造了一个小生境， 组织修复随着年龄的增长，分泌龛的成分丢失，导致骨愈合减少。我们 先前的联体共生和骨髓移植模型以及体外细胞培养研究已经证实 年轻的巨噬细胞龛能够改善老年小鼠的骨折修复和成骨细胞分化。 值得注意的是，在这些调查中，年轻化与经典激活，亲- 炎性，M1巨噬细胞在损伤部位，但增加交替激活，再生，M2 巨噬细胞为了用治疗方法概括这些发现，我们治疗了一小群老年人， 小鼠骨折损伤后不久注射Maresin 1。相对于溶媒对照，给药小鼠显示 减少，控制损伤后的炎症，这些小鼠的骨折骨痂含有更多的矿物质。 此外，用Maresin 1处理的巨噬细胞条件培养基改善了老化的成骨细胞 分化、基质生产和矿物形成。在这里提出的工作中，我们将确定 Maresin 1治疗改善骨折愈合的机制，并确定 由巨噬细胞分泌的小生境，其改善老化的成骨细胞功能。

ABSTRACT Bone fractures occur in 50% of the population causing significant morbidity and mortality and costing more than $20 billion in health care annually. Fracture repair is a complex process that involves numerous signaling molecules and cellular processes, all of which have not been fully identified. Factors, such as advanced age, can negatively affect this process thereby impairing recovery and proper bone healing. Our preliminary data indicate that macrophages recruited to the site of bone injury in young mice create a niche that leads to robust tissue repair. With age, the constituents of the secreted niche are lost resulting in diminished bone healing. Our previous parabiosis and bone marrow transplant models as well as in vitro cell culture studies have confirmed that the young macrophage niche is able to improve fracture repair and osteoblast differentiation in aged mice. Notable within these investigations, rejuvenation coincided with decreased numbers of classically activated, pro- inflammatory, M1 macrophages at the site of injury but increased alternatively activated, regenerative, M2 macrophages. To recapitulate these findings using a therapeutic approach, we treated a small cohort of aged mice with Maresin1 shortly after bone fracture injury. Relative to vehicle controls, treated mice displayed decreased, control inflammation after injury and the fracture calluses from these mice contained more mineral. Furthermore, media conditioned by macrophages treated with Maresin1 improved aged osteoblast differentiation, matrix production, and mineral formation. Within the proposed work here we will identify the mechanism by which Maresin1 treatment improves bone fracture healing and determine the constituents of the niche secreted by macrophages which improves aged osteoblast function.