Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Front Immunol. 2019 Apr 12;10:797. doi: 10.3389/fimmu.2019.00797. eCollection 2019.
Bone formation as well as bone healing capacity is known to be impaired in the elderly. Although bone formation is outpaced by bone resorption in aged individuals, we hereby present a novel path that considerably impacts bone formation and architecture: Bone formation is substantially reduced in aged individual owing to the experience of the adaptive immunity. Thus, immune-aging in addition to chronological aging is a potential risk factor, with an experienced immune system being recognized as more pro-inflammatory. The role of the aging immune system on bone homeostasis and on the bone healing cascade has so far not been considered. Within this study mice at different age and immunological experience were analyzed toward bone properties. Healing was assessed by introducing an osteotomy, immune cells were adoptively transferred to disclose the difference in biological vs. chronological aging. studies were employed to test the interaction of immune cell products (cytokines) on cells of the musculoskeletal system. In metaphyseal bone, immune-aging affects bone homeostasis by impacting bone formation capacity and thereby influencing mass and microstructure of bone trabeculae leading to an overall reduced mechanical competence as found in bone torsional testing. Furthermore, bone formation is also impacted during bone regeneration in terms of a diminished healing capacity observed in young animals who have an experienced human immune system. We show the impact of an experienced immune system compared to a naïve immune system, demonstrating the substantial differences in the healing capacity and bone homeostasis due to the immune composition. We further showed that mechanical stimulation changed the immune system phenotype in young mice toward a more naïve composition. While this rescue was found to be significant in young individuals, aged mice only showed a trend toward the reconstitution of a more naïve immune phenotype. Considering the immune system's experience level in an individual, will likely allow one to differentiate (stratify) and treat (immune-modulate) patients more effectively. This work illustrates the relevance of including immune diagnostics when discussing immunomodulatory therapeutic strategies for the progressively aging population of the industrial countries.
众所周知，老年人的骨形成和骨愈合能力受损。虽然在老年人中，骨形成超过骨吸收，但我们在此提出了一个新的途径，它对骨形成和结构有很大的影响：由于适应性免疫的经历，老年人的骨形成大大减少。因此，免疫衰老除了与年龄有关外，还是一个潜在的风险因素，因为经验丰富的免疫系统被认为更具炎症性。衰老免疫系统对骨内稳态和骨愈合级联反应的作用迄今尚未被考虑。在这项研究中，分析了不同年龄和免疫经验的小鼠的骨骼特性。通过引入截骨术来评估愈合，采用过继转移免疫细胞来揭示生物衰老与时间衰老的差异。采用研究来测试免疫细胞产物（细胞因子）与肌肉骨骼系统细胞的相互作用。在骺骨中，免疫衰老通过影响骨形成能力来影响骨内稳态，从而影响骨小梁的质量和微观结构，导致在骨扭转试验中发现的整体机械能力降低。此外，在骨再生过程中，骨形成也受到影响，表现为在具有经验性人类免疫系统的年轻动物中观察到的愈合能力降低。我们展示了经验性免疫系统与幼稚免疫系统的影响，由于免疫组成的不同，显示出愈合能力和骨内稳态的显著差异。我们进一步表明，机械刺激使年轻小鼠的免疫系统表型向更幼稚的组成转变。虽然在年轻个体中发现这种挽救是显著的，但老年小鼠仅表现出向更幼稚的免疫表型再构成的趋势。考虑到个体的免疫系统经验水平，可能会使人们能够更有效地对患者进行区分（分层）和治疗（免疫调节）。这项工作说明了在讨论针对工业化国家不断老龄化人口的免疫调节治疗策略时，包括免疫诊断的相关性。
