Depletion of cytotoxic (CD8+) T cells impairs implant fixation in rat cancellous bone

Hammerman

Muscle Ligaments and Tendons J

et al. 2021

Background. Macrophages are a heterogeneous cell population that plays an important role in the initiation of the inflammatory response to trauma as well as its resolution during healing. However, their role during Achilles tendon healing is unclear. The aim of this study was to investigate if macrophage reduction by using clodronate liposome injection would influence the mechanical properties of the healing tendon. Methods. The right Achilles tendon of 46 rats were transected and left to heal spontaneously (day 0). The reduction of macrophages during the inflammatory phase of tendon healing was studied by injecting clodronate liposomes day-3,-1 and 1. To study the early remodeling phase, clodronate was injected day 3, 5 and 7. The controls received saline and the rats were evaluated by mechanical testing day 7 and 12, respectively. Results. Clodronate injections during the inflammatory phase increased transverse area (p = 0.006) and stiffness (p = 0.044) day 7. In contrast, no significant effects were seen at day 12. Flow cytometry evaluation confirmed reduction of mature and polarized macrophages. Conclusions. Reduction of macrophages during the inflammatory phase of Achilles tendon healing influenced the mechanical properties, suggesting a regulatory role of macrophages during this phase.

Section: Discussionsupporting

confidence: 85%

Role of Macrophages During early Achilles Tendon Healing

Hammerman

Muscle Ligaments and Tendons J

et al. 2021

“…However, another group has found that deficiency in the adaptive immune system could result in accelerated fracture healing (32). In a sheep fracture model, cytotoxic T cells (CD8 + T cells) were accumulated in a considerably increased abundance in delayed fracture healing group accompanied with enhanced inflammation (33), while in a rat model of fracture, depletion of cytotoxic T cells by neutralizing antibody did not affect bone formation by reducing the implant pull-out force and stiffness (34). It was reported that B cells can secrete osteoprotegerin to inhibit osteoclastogenesis to maintain bone homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Long Non-coding RNAs in Traumatic Brain Injury Accelerated Fracture Healing

et al. 2021

It is commonly observed that patients with bone fracture concomitant with traumatic brain injury (TBI) had significantly increased fracture healing, but the underlying mechanisms were not fully revealed. Long non-coding RNAs (lncRNAs) are known to play complicated roles in bone homeostasis, but their role in TBI accelerated fracture was rarely reported. The present study was designed to determine the role of lncRNAs in TBI accelerated fracture via transcriptome sequencing and further bioinformatics analyses. Blood samples from three fracture-only patients, three fracture concomitant with TBI patients, and three healthy controls were harvested and were subsequently subjected to transcriptome lncRNA sequencing. Differentially expressed genes were identified, and pathway enrichment was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. High-dimensional data visualization by self-organizing map (SOM) machine learning was applied to further interpret the data. An xCell method was then used to predict cellular behavior in all samples based on gene expression profiles, and an lncRNA–cell interaction network was generated. A total of 874 differentially expressed genes were identified, of which about 26% were lncRNAs. Those identified lncRNAs were mainly enriched on TBI-related and damage repair-related pathways. SOM analyses revealed that those differentially expressed lncRNAs could be divided into three major module implications and were mainly enriched on transcriptional regulation and immune-related signal pathways, which promote us to further explore cellular behaviors based on differentially expressed lncRNAs. We have predicted that basophils, CD8+ T effector memory cells, B cells, and naïve B cells were significantly downregulated, while microvascular endothelial cells were predicted to be significantly upregulated in the Fr/TBI group, was the lowest and highest, respectively. ENSG00000278905, ENSG00000240980, ENSG00000255670, and ENSG00000196634 were the most differentially expressed lncRNAs related to all changes of cellular behavior. The present study has revealed for the first time that several critical lncRNAs may participate in TBI accelerated fracture potentially via regulating cellular behaviors of basophils, cytotoxic T cells, B cells, and endothelial cells.

“…This method has been described in detail previously. 4 Histological Examination. Twelve rats were used for histological imaging with normal hematoxylin and eosin staining on saline-and dexamethasone-treated tendons.…”

Section: Standard Proceduresmentioning

confidence: 99%

Dexamethasone Enhances Achilles Tendon Healing in an Animal Injury Model, and the Effects Are Dependent on Dose, Administration Time, and Mechanical Loading Stimulation

2022

Self Cite

Background: Corticosteroid treatments such as dexamethasone are commonly used to treat tendinopathy but with mixed outcomes. Although this treatment can cause tendon rupture, it can also stimulate the tendon to heal. However, the mechanisms behind corticosteroid treatment during tendon healing are yet to be understood. Purpose: To comprehend when and how dexamethasone treatment can ameliorate injured tendons by using a rat model of Achilles tendon healing. Study Design: Controlled laboratory study. Methods: An overall 320 rats were used for a sequence of 6 experiments. We investigated whether the drug effect was time-, dose-, and load-dependent. Additionally, morphological data and drug administration routes were examined. Healing tendons were tested mechanically or used for histological examination 12 days after transection. Blood was collected for flow cytometry analysis in 1 experiment. Results: We found that the circadian rhythm and drug injection timing influenced the treatment outcome. Dexamethasone treatment at the right time point (days 7-11) and dose (0.1 mg/kg) significantly improved the material properties of the healing tendon, while the adverse effects were reduced. Local dexamethasone treatment did not lead to increased peak stress, but it triggered systemic granulocytosis and lymphopenia. Mechanical loading (full or moderate) is essential for the positive effects of dexamethasone, as complete unloading leads to the absence of improvements. Conclusion: We conclude that dexamethasone treatment to improve Achilles tendon healing is dose- and time-dependent, and positive effects are perceived even in a partly unloaded condition. Clinical Relevance: These findings are promising from a clinical perspective, as the positive effect of this drug was seen even when given at lower doses and in a moderate loading condition, which better mimics the load level in patients with tendon ruptures.