Neutralization of HMGB1 improves fracture healing and γδ T lymphocyte counts at the fracture site in a polytrauma rat model

Muire, Preeti J.; Avila, Joshua J.; Lofgren, Alicia L; Wenke, Joseph C.

doi:10.1186/s40634-022-00453-3

Cited by 7 publications

(3 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When this proinflammatory upstream cytokine is blocked by an HBGB1 antibody, healing is restored. 20 Importantly, blocking inflammation upstream restores RAGE and TLR4 surface expression on circulating T cells and increases the number of gdTCR 1 T cells at the fracture site. The observations provide rich potential targets for future interventions.…”

Section: Immune Dysregulation Causes Impaired Wound and Fracture Healingmentioning

confidence: 99%

The local and systemic effects of immune function on fracture healing

Evans,

Giannoudis,

Leucht

et al. 2024

OTA International

Self Cite

View full text Add to dashboard Cite

The immune system plays an integral role in the regulation of cellular processes responsible for fracture healing. Local and systemic influences on fracture healing correlate in many ways with fracture-related outcomes, including soft tissue healing quality and fracture union rates. Impaired soft tissue healing, restricted perfusion of a fracture site, and infection also in turn affect the immune response to fracture injury. Modern techniques used to investigate the relationship between immune system function and fracture healing include precision medicine, using vast quantities of data to interpret broad patterns of inflammatory response. Early data from the PRECISE trial have demonstrated distinct patterns of inflammatory response in polytrauma patients, which thereby directly and indirectly regulate the fracture healing response. The clearly demonstrated linkage between immune function and fracture healing suggests that modulation of immune function has significant potential as a therapeutic target that can be used to enhance fracture healing.

show abstract

Section: Immune Dysregulation Causes Impaired Wound and Fracture Healingmentioning

confidence: 99%

The local and systemic effects of immune function on fracture healing

Evans,

Giannoudis,

Leucht

et al. 2024

OTA International

Self Cite

View full text Add to dashboard Cite

show abstract

“…While the role of HMGB1 and S100 has been previously studied in PT patients with delayed bone healing scenarios, the role of cell free mtDNA and associated pathways are yet to be explored in the context of PT. In a previous study, we demonstrated that by transient neutralization of HMGB1 and its associated pro‐inflammatory pathways we could achieve improved bone fracture healing in a PT rat model [7]. Next, we questioned whether DAMP activated pathways, different from those activated by HMGB1, when modulated can regulate confounding immune responses and maintain proper homeostasis to promote bone healing.…”

Section: Introductionmentioning

confidence: 99%

Fracture healing in a polytrauma rat model is influenced by mtDNA:cGAS complex mediated pro‐inflammation

Muire,

Lofgren,

Shiels

et al. 2023

J. exp. orthop.

Self Cite

View full text Add to dashboard Cite

Purpose The mitochondrial DNA (mtDNA) activated cyclic guanosine monophosphate–adenosine monophosphate synthase—stimulator of interferon genes (cGAS-STING) signaling pathway is a key player in mediating immune responses in autoimmune disorders and cancer. However, its role in severe trauma associated fracture healing is unknown. This study investigated if the cGAS-STING signaling pathway contributes to delayed bone healing in polytrauma (PT) fractures. Methods For preliminary analyses, therapeutic dosage of RU.521 (cGAS inhibitor) (n = 2) was determined in C57BL/6 J mice by mass spectrometry, and IFNβ expression levels in serum and bronchioalveolar fluid (BALF) at 6 and 24 h (h) in RU.521/vehicle + mtDNA injected mice (n = 3/treatment and time point) was measured by ELISA. In the main study, plasma mtDNA was quantified by qPCR in a clinically relevant delayed fracture healing PT rat model with burn injury, blunt trauma, and a femoral fracture at 3 h post-trauma (hpt). Next, PT rats received either RU.521 (12 mg/kg in povidone; n = 8) or vehicle (povidone only; n = 5) immediately after injury and were followed up for 5 weeks post-trauma to assess bone regeneration by radiography and histology. Results IFNβ levels were significantly decreased only at 24 h in BALF of RU.521 treated mice. At 3hpt mtDNA was significantly elevated in PT rats compared to rats without injury. When treated with RU.521, PT rats showed improvement in bone healing compared to vehicle control PT rats. Conclusions These data reveal that the cGAS-STING signaling pathway influences trauma-induced delayed bone healing. However, further evaluation of this pathway at the cellular and molecular levels to augment PT associated detrimental effects is needed.

show abstract

“…[13,14] In the latest study, HMGB1 was found to promote fracture healing in rat fracture models. [15,16] However, so far, no clinical studies focus on the role of HMGB1 in intertrochanteric fracture development and prognosis.…”

Section: Introductionmentioning

confidence: 99%

Serum HMGB1 levels and its clinical significance in elderly patients with intertrochanteric fractures after intramedullary fixation surgery

Zhao

Zhang

et al. 2023

Medicine

View full text Add to dashboard Cite

Background: Intramedullary fixation is a valuable alternative for the treatment of intertrochanteric fractures. However, further development of new biomarkers to predict the prognosis of the patient is still needed for timely and effective treatment and intervention. The present study aimed to explore the serum high-mobility group box 1 (HMGB1) levels in the prognosis of intertrochanteric fracture patients and its correlation with clinical results. Methods: The present prospective cohort study recruited 115 intertrochanteric fracture patients who were admitted from January 2015 to December 2019. All patients were evaluated preoperatively and treated (proximal femoral nail antirotation or intramedullary proximal femoral nail) by the same team. The serum HMGB1, interleukin-6, interleukin-1β, tumor necrosis factor α, and C-reactive protein levels were measured by enzyme-linked immunosorbent assay. Demographic and clinical data of all patients were collected. Harris score was used to assess the prognosis of intertrochanteric fracture patients after 6 months of treatment. Statistical analysis was conducted using SPSS software with P < .05 as statistically different. Results: The time of the operation and the amount of bleeding in intramedullary proximal femoral nail were remarkably elevated compared with the proximal femoral nail antirotation group (P < .05). The age, proportion of complications and visual analogue score VAS after 72 hours of surgery in the Harris score < 80 group were remarkably increased compared with Harris score ≥ 80 group (P < .05). In addition, we found that the serum HMGB1 levels in Harris score < 80 group were markedly elevated than the patients in Harris score ≥ 80 group at all time points (P < .05). The results showed that the serum HMGB1 levels at postoperative 48 hours had the highest predictive value for predicting poor prognosis in intertrochanteric fracture patients. It was found that HMGB1, age and VAS after 72 hours of surgery were the risk factors for poor prognosis of intertrochanteric fracture patients. Conclusion: This study showed that the serum HMGB1 levels was significantly decreased in intertrochanteric fracture patients with bad prognoses. This study may provide a new approach to screening intertrochanteric fracture patients with worse prognoses in advance.

show abstract

Neutralization of HMGB1 improves fracture healing and γδ T lymphocyte counts at the fracture site in a polytrauma rat model

Cited by 7 publications

References 46 publications

The local and systemic effects of immune function on fracture healing

The local and systemic effects of immune function on fracture healing

Fracture healing in a polytrauma rat model is influenced by mtDNA:cGAS complex mediated pro‐inflammation

Serum HMGB1 levels and its clinical significance in elderly patients with intertrochanteric fractures after intramedullary fixation surgery

Contact Info

Product

Resources

About