Symptomatic heterotopic ossification after very severe traumatic brain injury in 114 patients: Incidence and risk factors

Simonsen, Louise Lau; Sonne‐Holm, Stig; Krasheninnikoff, Michael; Engberg, Aase W.

doi:10.1016/j.injury.2007.03.019

Cited by 86 publications

(49 citation statements)

References 18 publications

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“…This threshold may be related to several subsequent events associated with tissue damage such as the size of the immunological response, the degree of vascular damage incurred, and/or the resulting local oxygen tension following injury. It may also be hypothesised that a certain concentration of chemokines must be present in order to signal the recruitment of resident or circulating stem cells, and that this is related to the severity of trauma [36]. The need for further work to characterise these cells comprehensively is now of great importance if the true identity of this mesenchymal population and its role in HO is to be elucidated.…”

Section: Mesoderm Mesenchymal Stem Cellsmentioning

confidence: 99%

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

et al. 2015

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Section: Mesoderm Mesenchymal Stem Cellsmentioning

confidence: 99%

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

et al. 2015

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“…Thus our data suggest that NHO formation after SCI is not via endochondral bone formation and most likely is formed by intramembranouse pathway as occurs in POH patients [137]. It has been published that degree of severity of NHO depends on the completeness of SCI [132,133]. Our data confirmed these findings.…”

Section: Discussionsupporting

confidence: 87%

“…Considering that incidence rate of NHO is higher in patients with associated trauma or sepsis such as infected war wounds or following a car crash [131][132][133] we decided to replace intensive muscle injury caused by cardiotoxin injection by crush injury of 2 different mechanical loads, which is closer to mechanisms of multiple trauma in patients with SCI.…”

Section: Physiological Model Of Nhomentioning

confidence: 99%

Understanding heterotopic ossification after spinal cord injury

Kulina¹

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Neurological heterotopic ossification (NHO) is a frequent complication of spinal cord and traumatic brain injuries (15-25% of patients) and manifests as abnormal ossification of soft tissues near joints. NHO is very debilitating and further delays rehabilitation as it causes pain, joint deformation and ankylosis and vascular and nerve compression. In the absence of an animal model the mechanisms leading to NHO are unknown and consequently there is no preventive treatment. The only effective approach to eliminate HO is complicated and expensive surgical resection. However these surgeries are delicate and can be challenging as they are performed once the NHO are mature, often large and incapacitating entrapping large blood vessels and nerves.To elucidate NHO pathophysiology, we have developed the first animal model of NHO in genetically unmodified mice. Mice underwent a spinal cord transection (SCI); muscular inflammation was induced by intramuscular injection of cardiotoxin in limbs (IM-CTX).Formation of NHO was followed by μCT and immunohistology.SCI alone or muscular inflammation alone did not induce NHO in mice. The combination of both SCI and muscular inflammation was necessary to induce NHO. This is consistent with clinical observations as NHO incidence is higher in patients with severe trauma or concomitant infection. Abundant F4/80 + macrophages, which can provide pro-anabolic support in bone formation, were detected within the inflamed muscle and associated with areas of intramuscular bone formation (confirmed by von Kossa and collagen type 1 staining). In vivo depletion of phagocytic macrophages with clodronate-loaded liposomes prevented NHO formation whereas Zoledronate treatment exacerbated NHO. This supports our hypothesis that macrophage-mediated inflammation is a key activator of NHO following SCI. To further identify the source and type of macrophages, involved in the bone formation after SCI and test some potential treatment options different knock-out mouse models were investigated. My data suggest that local muscle residential macrophages potentially play an important role in NHO.In addition we identified several populations of muscle progenitor cells that are prone to osteogenic differentiation in vitro. These data suggest that the mesenchymal progenitors that differentiate into osteoblasts in HO following spinal cord injury are already present in healthy muscles and therefore can be derived from local muscle progenitor cells rather than being recruited from the remote site, such as bone marrow.iii Finally we investigated why SCI was necessary for NHO development. My hypothesis was that SCI causes release of systemic factors priming NHO. In support of this, I showed that NHO developed in non-paralysed inflamed front limbs of mice with SCI. Also, blood plasma from mice with SCI and IM-CTX induced osteogenic differentiation of cultured muscle mesenchymal progenitor cells (mMPC) sorted from naïve mice. This suggests that systemic factors facilitating NHO, such as substance P and G-CSF are ...

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“…Recurrent mutations in the BMP type-1 receptor, activin receptor IA (ACVR1), and local changes in the expression of BMP-4 and its receptor (BMPR1A) have been linked to the rare genetic disorder fibrodysplasia ossificans progressiva [11,13,18,20,26]. The more common acquired forms of HO frequently occur as a complication of THA, elbow or acetabular fractures requiring surgical treatment, soft tissue injury secondary to trauma or deep muscle dissection, and traumatic brain or spinal cord injuries [3,7,8,25,49].…”

Section: Introductionmentioning

confidence: 99%

Osteogenic Gene Expression Correlates With Development of Heterotopic Ossification in War Wounds

Evans

Potter

Brown

et al. 2013

Clin Orthop Relat Res

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Background Heterotopic ossification (HO) is a frequent complication of modern wartime extremity injuries. The biological mechanisms responsible for the development of HO in traumatic wounds remain elusive. Question/purposes The aims of our study were to (1) characterize the expression profile of osteogenesis-related gene transcripts in traumatic war wounds in which HO developed; and (2) determine whether expression at the mRNA level correlated with functional protein expression and HO formation. Methods Biopsy specimens from 54 high-energy penetrating extremity wounds obtained at the initial and final surgical débridements were evaluated. The levels of selected osteogenic-related gene transcripts from RNA extracts were assessed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. As a result of its key role in osteogenesis, the concentration of BMP-2 in the effluent of 29 wounds also was determined. Conclusions Important differences exist in the osteogenic gene expression profile of wounds in which HO developed compared with wounds in which it did not develop. The upregulation of multiple osteogenesis-related gene transcripts indicates the presence of a proosteogenic environment necessary for ectopic bone formation in traumatic wounds.

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Symptomatic heterotopic ossification after very severe traumatic brain injury in 114 patients: Incidence and risk factors

Cited by 86 publications

References 18 publications

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

Understanding heterotopic ossification after spinal cord injury

Osteogenic Gene Expression Correlates With Development of Heterotopic Ossification in War Wounds

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