Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany.
Berlin Institute of Health Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany.
Front Immunol. 2019 Oct 18;10:2443. doi: 10.3389/fimmu.2019.02443. eCollection 2019.
Fracture repair is initiated by a multitude of immune cells and induction of an inflammatory cascade. Alterations in the early healing response due to an aged adaptive immune system leads to impaired bone repair, delayed healing or even formation of non-union. However, immuno-senescence is not limited to the adaptive immunity, but is also described for macrophages, main effector cells from the innate immune system. Beside regulation of pro- and anti-inflammatory signaling, macrophages contribute to angiogenesis and granulation tissue maturation. Thus, it seems likely that an altered macrophage function due to aging may affect bone repair at various stages and contribute to age related deficiencies in bone regeneration. To prove this hypothesis, we analyzed the expression of macrophage markers and angiogenic factors in the early bone hematoma derived from young and aged osteotomized Spraque Dawley rats. We detected an overall reduced expression of the monocyte/pan-macrophage markers CD14 and CD68 in aged rats. Furthermore, the analysis revealed an impaired expression of anti-inflammatory M2 macrophage markers in hematoma from aged animals that was connected to a diminished revascularization of the bone callus. To verify that the age related disturbed bone regeneration was due to a compromised macrophage function, CD14+ macrophage precursors were transplanted locally into the osteotomy gap of aged rats. Transplantation rescued bone regeneration partially after 6 weeks, demonstrated by a significantly induced deposition of new bone tissue, reduced fibrosis and significantly improved callus vascularization.
骨折修复是由大量免疫细胞启动的,并诱导炎症级联反应。由于适应性免疫系统老化,早期愈合反应发生改变,导致骨修复受损、愈合延迟,甚至形成骨不连。然而,免疫衰老不仅限于适应性免疫,也存在于巨噬细胞中,巨噬细胞是先天免疫系统的主要效应细胞。除了调节促炎和抗炎信号外,巨噬细胞还参与血管生成和肉芽组织成熟。因此,由于衰老导致的巨噬细胞功能改变可能会影响骨修复的各个阶段,并导致与年龄相关的骨再生缺陷。为了验证这一假说,我们分析了来自年轻和年老去骨切开 Spraque Dawley 大鼠的早期骨血肿中的巨噬细胞标记物和血管生成因子的表达。我们发现在老年大鼠中,单核细胞/泛巨噬细胞标记物 CD14 和 CD68 的总体表达减少。此外,分析显示,来自老年动物血肿中的抗炎 M2 巨噬细胞标记物的表达受损,与骨痂的血管再形成减少有关。为了验证与年龄相关的骨再生受损是由于巨噬细胞功能受损所致,我们将 CD14+巨噬细胞前体局部移植到老年大鼠的骨切开间隙中。6 周后,移植部分挽救了骨再生,表现为新骨组织沉积明显增加,纤维化减少,骨痂血管化明显改善。