Experience in the Adaptive Immunity Impacts Bone Homeostasis, Remodeling, and Healing

Abstract

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. In vitro 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 in vivo 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.

Limbostomy: Longitudinal Intravital Microendoscopy in Murine Osteotomies

“…To enable visualization of bone regeneration processes, we aimed to access the center of the femoral long bone in an osteotomy. Based on the average femoral bone diameter of 1,415 μm, calculated from μCT data of 3‐month‐old mice (as published in Bucher et al) , we glued the lens into the tubing at 900 μm protruding from the bottom of the fixation plate. This includes 700 μm bone and bone marrow as well as 200 μm offset between the plate and the bone surface, before the lens enters the bone.…”

“…However, certain risk factors like age or metabolic disorders can delay or even impede the healing process significantly, reflected in fracture healing disorders which occur in 5–10% of patients . In order to further define risk factors and design patient‐oriented therapeutic strategies, a detailed understanding of the processes underlying bone regeneration is necessary.…”

“…However, mainly due to a lack of appropriate tools and technology, the details of this interplay, especially its spatiotemporal aspects, are not fully understood. Histological analyses, which demonstrated a role for the innate and adaptive arms of the immune system, have been performed. These analyses represent ex vivo snapshots of the tissue state taken from individuals at defined time points and have laid the foundation for a comprehensive analysis of the cellular composition at the injury site at various phases of bone regeneration.…”

HIF-stabilization prevents delayed fracture healing

“…In order to delineate a therapeutic option for fracture healing disorders based on HIF-stabilization for e.g. patients with a delayed healing potential due to immunological and/or angiogenic constraints (31,59), we evaluated the potential of an appropriate delivery/release system. Based on the observation that the fracture hematoma obtained from immune-suppressed patients revealed an upregulated inflammatory profile during the initial phase of fracture healing , we tested dendritic polyglycerol sulfate (dPGS)-based polyethylene glycol-dicyclooctyne (PEG-DIC) hydrogels, which have been developed to act antiinflammatory (31,32,(60)(61)(62).…”

In Vivo Validation of Spray-Dried Mesoporous Bioactive Glass Microspheres Acting as Prolonged Local Release Systems for BMP-2 to Support Bone Regeneration

“…The capacity for complete bone healing is known to decline with increasing age [ 5 , 6 ], as a consequence of a higher prevalence of comorbidities and a generally more pro-inflammatory state (“inflamm-aging”) [ 7 ]. The total number of impaired healing cases, as well as its prevalence, are expected to rise in light of the demographic change and a continuous increase in life expectancy [ 8 , 9 , 10 ], resulting in a growing medical need for strategies to restore healing in compromised settings.…”