Brain injury severity and autonomic dysregulation accurately predict                 heterotopic ossification in patients with traumatic brain injury

Hendricks, Henk T.; Geurts, Alexander C. H.; Ginneken, Bart C. van; Heeren, Anita J.; Vos, Pieter E.

doi:10.1177/0269215507075260

Cited by 86 publications

(67 citation statements)

References 20 publications

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“…Because traumatic brain injury is an additional risk factor for HO [7,14], high-energy wartime extremity injuries place warwounded patients at an increased risk of developing debilitating heterotopic lesions [10]. Although the pathophysiology of HO is not completely clarified, traumatic insults impacting the neuromuscular system are known to initiate an inflammatory cascade leading to heterotopic bone formation.…”

Section: Introductionmentioning

confidence: 99%

Botulinum Toxin-induced Muscle Paralysis Inhibits Heterotopic Bone Formation

Ausk

Gross

Bain

2015

Clinical Orthopaedics &Amp; Related Research

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Background Short-term muscle atrophy induced by botulinum toxin A (BTxA) has been observed to impair osteogenesis in a rat closed femur fracture model. However, it is unclear whether the underlying mechanism is a direct effect of BTxA on muscle-bone interactions or an indirect effect that is driven by skeletal unloading. Because skeletal trauma in the closed fracture model also leads to disuse atrophy, we sought to mitigate this confounding variable by examining BTxA effects on muscle-bone interactions in two complementary in vivo models in which osteogenesis is induced in the absence of skeletal unloading. The overall aim of this study was to identify a potential strategy to inhibit pathological bone formation and heterotopic ossification (HO). Questions/purposes (1) Does muscle paralysis inhibit periosteal osteogenesis induced by a transcortical defect? (2) Does muscle paralysis inhibit heterotopic bone formation stimulated by intramuscular bone morphogenetic protein (BMP) injection? Methods Focal osteogenesis was induced in the right hindlimb of mice through surgical initiation of a small transcortical defect in the tibia (fracture callus; n = 7/group) or intramuscular injection of BMP-2 (HO lesion; n = 6/group), both in the presence/absence of adjacent calf paralysis. High-resolution micro-CT images were obtained in all experimental groups 21 days postinduction and total volume (ie, perimeter of periosteal callus or HO lesion) and bone volume (calcified tissue within the total volume) were quantified as primary outcome measures. Finally, these outcome measures were compared to determine the effect of muscle paralysis on inhibition of local osteogenesis in both studies.Results After a transcortical defect, BTxA-treated mice showed profound inhibition of osteogenesis in the periosteal fracture callus 21 days postsurgery compared with saline-treated mice (total volume: 0.08 ± 0.06 versus 0.42 ± 0.11 mm 3 , p \ 0.001; bone volume: 0.07 ± 0.05 versus 0.32 ± 0.07 mm 3 , p \ 0.001). Similarly, BMP-2-induced HO formation was inhibited by adjacent muscle paralysis at the same time point (total volume: 1.42 ± 0.31 versus 3.42 ± 2.11 mm 3 , p = 0.034; bone volume: 0.68 ± 0.18 versus 1.36 ± 0.79 mm 3 , p = 0.045). Conclusions Our data indicate that BTxA-induced neuromuscular inhibition mitigated osteogenesis associated with both a transcortical defect and BMP-2-induced HO. Clinical Relevance Focal neuromuscular inhibition represents a promising new approach that may lead to a new clinical intervention to mitigate trauma-induced HO, a healthcare challenge that is severely debilitating for civilian and war-wounded populations, is costly to both the patient and the healthcare system, and currently lacks effective treatments.

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Section: Introductionmentioning

confidence: 99%

Botulinum Toxin-induced Muscle Paralysis Inhibits Heterotopic Bone Formation

Ausk

Gross

Bain

2015

Clinical Orthopaedics &Amp; Related Research

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“…However, HO is also seen following central nervous system (CNS) injuries with or without limb injuries [5][6]. Previous studies have reported that about 10 to 37 percent of patients with traumatic brain injury [7][8][9] and about 20 to 30 percent of patients with spinal cord injury (SCI) [10][11] develop HO after CNS injuries.…”

Section: Introductionmentioning

confidence: 99%

Novel mouse model of spinal cord injury-induced heterotopic ossification

et al. 2014

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Abstract-Heterotopic ossification (HO) develops in about 20% to 30% of patients with spinal cord injury (SCI) and significantly impairs their rehabilitation. There is no effective prevention or treatment for this condition at this time. Our current understanding of its etiology and pathophysiology is limited partially due to the lack of clinically relevant animal models. In this study, we report a novel mouse model of SCI-induced HO by administering a subthreshold dose of bone morphogenetic protein (BMP)-2 to muscles in mice after SCI. Microcomputed tomography scanning showed that an intramuscular injection of 0.25 micrograms of BMP-2 causes significant HO in mice with SCI but not in control (sham surgery) mice. Our analysis of gene expression showed significantly increased BMP signaling in quadriceps following SCI, suggesting that BMP signaling may play a role in SCI-induced HO. Administering 0.25 micrograms of BMP-2 to the front arms of the mice with SCI also results in the development of significant HO but not in control mice. This suggests that SCI causes a systematic osteogenic effect, which is not limited to paralyzed limbs. This novel mouse model will serve as a powerful tool in exploring the molecular mechanisms of SCI-induced HO, which may lead to novel treatment for this disease.

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“…Heterotopic ossification (HO) is a formation of lamellar bone in soft tissues following brain or spinal injury (Hendricks et al 2007). HO usually involves the large joints of the body such as the hip, elbow, shoulders, and knees.…”

Section: Definitionmentioning

confidence: 99%