C5aR‐antagonist significantly reduces the deleterious effect of a blunt chest trauma on fracture healing

Recknagel, Stefan; Bindl, Ronny; Kurz, Julian; Wehner, Tim; Schoengraf, Philipp; Ehrnthaller, Christian; Qu, Hongchang; Gebhard, Florian; Huber‐Lang, Markus; Lambris, John D.; Claes, Lutz; Ignatius, Anita

doi:10.1002/jor.21561

Cited by 47 publications

(61 citation statements)

References 40 publications

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“…Typical periosteal callus formation could be observed. These formations are in good accordance with the reports found in the literature where the effect of BMP on the periosteal callus formation within the fi rst 4 weeks post osteotomy has been described (Schmidmaier et al, 2002;Wildemann et al, 2011;Wulsten et al, 2011).…”

Section: B Preininger Et Alsupporting

confidence: 91%

“…In our model, the BMP stimulated group showed complete bone healing within 6 weeks while the untreated group resulted in an impaired healing situation. These observations go along with the experiments of Wildemann et al (Wildemann et al, 2011), where an intramedullary nail coated with BMP was capable of rescuing a non union in a rat model. The early formations of mineralised callus tissue support the results from Wulsten et al (Wulsten et al, 2011) where BMP induced a very early callus formation and thereby stiffening these callus formations.…”

Section: Discussionsupporting

confidence: 78%

“…To date, bone morphogenetic proteins (BMP) (BMP2,) are the only drugs available to enhance bone healing next to traditional techniques which aim to locally supplement bone material through either autologous or allogeneous bone product grafting (Wildemann et al, 2011). Several new drugs and "bioproducts", however, are currently in the stage of development (Chen et al, 2010;Harvey et al, 2010;Tare et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Factors related to reduced bone mineral density and thereby to higher fracture risk (Demir et al, 2008) as well as to limited bone www.ecmjournal.org B Preininger et al Healing potential in a long bone model healing capacity, like age (Meyer et al, 2001;Meyer et al, 2006;Strube et al, 2008b) and gender (David et al, 2006;Parker et al, 2007;Yamada et al, 2007Strube et al, 2009 are inherently considered in osteoporosis models (Kalu, 1991;Duque et al, 2009); yet these factors have not been taken into account so far in bone healing models. The hypotheses of this work were: i) that in 12-monthold female, ex-breeder Sprague Dawley rats, a 2 mm femoral OT gap stabilised by an external fi xator device would not heal within 6 weeks, whereas by the local application of BMP within a blood clot bony bridging would be achieved (Govender et al, 2002;Einhorn et al, 2003;Wildemann et al, 2011); ii) that the delivery of an autologous blood clot would not alter the healing outcome compared to the group in which native haematoma was allowed to form following the OT.…”

Section: Introductionmentioning

confidence: 99%

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An experimental setup to evaluate innovative therapy options for the enhancement of bone healing using BMP as a benchmark – a pilot study

Preininger

Gerigk²,

Brückner³

et al. 2012

eCM

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Critical or delayed bone healing in rat osteotomy (OT) models is mostly achieved through large defects or instability. We aimed to design a rat OT model for impaired bone healing based on age, gender and parity. The outcome should be controllable through variations of the haematoma in the OT including a bone morphogenetic protein (BMP) 2 guided positive control.Using external fi xation to stabilise femoral a 2 mm double OT in 12 month old, female Sprague Dawley rats after a minimum of 3 litters healing was characterised following in situ haematoma formation (ISH-group)), transplantation of a BMP charged autologous blood clot (BMP-group) and the artifi cial blood clot only (ABC-group) into the OT-gap. In vivo micro-computer tomography (μCT) scans were performed after 2, 4 and 6 weeks. After 6 weeks specimens underwent histological analyses.In μCT examinations and histological analyses no bony bridging was observed in all but one animal in the ISHgroup. In the BMP group complete bridging was achieved in all animals. The ABC-group showed less mineralised tissue formation and smaller bridging scores during the course of healing than the ISH-group.In this pilot study we introduce a model for impaired bone healing taking the major biological risk factors into account. We could show that the in situ fracture haematoma is essential for bone regeneration. Using BMP as a positive control the presented experimental setup can serve to evaluate innovative therapeutical concepts in long bone application.

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Section: B Preininger Et Alsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

An experimental setup to evaluate innovative therapy options for the enhancement of bone healing using BMP as a benchmark – a pilot study

Preininger

Gerigk²,

Brückner³

et al. 2012

eCM

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“…Several studies were also able to identify an involvement of the complement cascade in the process of fracture healing [5, 10, 11]. …”

Section: Introductionmentioning

confidence: 99%

C5aR inhibition in the early inflammatory phase does not affect bone regeneration in a model of uneventful fracture healing

et al. 2016

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BackgroundRecent studies were able to demonstrate involvement of the complement cascade in bone biology. Further studies analyzed the role of complement in traumatic injuries and demonstrated negative effects after excessive systemic activation of the inflammatory response with early abrogation of complement activation after application of a C5aR-antagonist exerting beneficial effects upon bone regeneration. In contrast, own fracture healing experiments with complement-deficient animals implied a crucial role of the complement cascade for sufficient fracture healing.MethodsTo analyze the effect of a short abrogation of the complement system in the local process of fracture healing, a fracture healing experiment with wild-type mice (C57BL6), femoral osteotomy, consecutive external fixation for 21 days and blockade of the early complement activation (C5aRA) directly after trauma and after 12 h was performed. Control animals received a peptide without any biological effects. After 1–3 days, the inflammatory response was monitored with IL-6 immunostaining, serum analyses of C5a and after 3 days with histological evaluation of PMN. Fracture healing was examined with biomechanical, radiological and histological methods after 21 days.ResultsWhile a decrease of the early inflammatory response was seen on day 1 of the C5aRA-treated group regarding immunostaining for IL-6 and after 3 days in the histological evaluation of PMN, no significant differences were demonstrated between both experimental groups after 21 days in the biomechanical, radiological and histological evaluation.ConclusionsThe present results demonstrate that the short-term inhibition of complement activation immediately after fracture does not significantly affect bone regeneration in an experimental model of regular fracture healing. Whereas other studies demonstrated that the early posttraumatic blockade of the C5aR improves fracture healing in a scenario of combined trauma, the present findings implicate that the same treatment has no effect in uneventful bone healing.

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Crepuscular rays — The bright side of complement after tissue injury

Mannes,

Savukoski,

Ignatius

et al. 2024

Eur J Immunol

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Acute injuries trigger an intense activation of the body's defense mechanisms aiming to limit damage and initiate healing. Among the crucial components of the intravascular immune system, the complement system plays a significant role in traumatic injuries, albeit often negatively. It has been suggested that excessive activation of the complement system, transitioning from a localized and timed response to a systemic one, can lead to a loss of its host‐protective characteristics. Complement activation products have been associated with the severity of injuries, which sometimes serve as predictors for the onset of organ dysfunctions. Animal studies utilizing complement‐targeting agents have provided the basis for considering complement in the management of traumatic injuries in humans. However, numerous studies suggest that the spatial and temporal aspects of complement inhibition are crucial for its efficacy. Understanding the underlying mechanism of the injury is essential to determine where, when, and whether complement inhibition is warranted. Despite the detrimental effects of uncontrolled complement activation, its regulated activation may contribute to essential aspects of healing, such as waste removal and regeneration. This review focuses on the beneficial roles of complement activation in trauma, which are often overlooked or given less consideration but are of immense importance.

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C5aR‐antagonist significantly reduces the deleterious effect of a blunt chest trauma on fracture healing

Cited by 47 publications

References 40 publications

An experimental setup to evaluate innovative therapy options for the enhancement of bone healing using BMP as a benchmark – a pilot study

An experimental setup to evaluate innovative therapy options for the enhancement of bone healing using BMP as a benchmark – a pilot study

C5aR inhibition in the early inflammatory phase does not affect bone regeneration in a model of uneventful fracture healing

Crepuscular rays — The bright side of complement after tissue injury

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