Relationship between heterotopic ossification and traumatic brain injury

Huang, Huan; Cheng, Wenxiang; Hu, Yiping; Chen, Jianhai; Zheng, Zheng-Tan; Zhang, Peng

doi:10.1016/j.jot.2017.10.002

Cited by 47 publications

(24 citation statements)

References 97 publications

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“…Clinical manifestations include increased joint stiffness, limited range of motion, swelling, and pain, all of which can result in severe functional limitations [2]. Although there is an uncommon hereditary disease called fibrodysplasia ossificans progressiva (FOP) that causes HO, most cases result from brain or spinal cord injury (“neurogenic HO”, NHO), local trauma such as orthopedic surgery, muscular trauma, fractures, severe burns (“traumatic HO”), or both processes [3–7]. Chalmers et al proposed that three conditions must be met for the development of HO: the presence of a permissive environment, an osteogenic progenitor cell, and an inducing factor [8].…”

Section: Introductionmentioning

confidence: 99%

Muscle injury-induced hypoxia alters the proliferation and differentiation potentials of muscle resident stromal cells

et al. 2019

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Background: Trauma-induced heterotopic ossification (HO) is a complication that develops under three conditions: the presence of an osteogenic progenitor cell, an inducing factor, and a permissive environment. We previously showed that a mouse multipotent Sca1 + CD31 − Lin − muscle resident stromal cell (mrSC) population is involved in the development of HO in the presence of inducing factors, members of the bone morphogenetic protein family. Interestingly, BMP9 unlike BMP2 causes HO only if the muscle is damaged by injection of cardiotoxin. Because acute trauma often results in blood vessel breakdown, we hypothesized that a hypoxic state in damaged muscles may foster mrSCs activation and proliferation and trigger differentiation toward an osteogenic lineage, thus promoting the development of HO. Methods: Three-to-six-month-old male C57Bl/6 mice were used to induce muscle damage by injection of cardiotoxin intramuscularly into the tibialis anterior and gastrocnemius muscles. mrSCs were isolated from damaged (hypoxic state) and contralateral healthy muscles and counted, and their osteoblastic differentiation with or without BMP2 and BMP9 was determined by alkaline phosphatase activity measurement. The proliferation and differentiation of mrSCs isolated from healthy muscles was also studied in normoxic incubator and hypoxic conditions. The effect of hypoxia on BMP synthesis and Smad pathway activation was determined by qPCR and/or Western blot analyses. Differences between normally distributed groups were compared using a Student's paired t test or an unpaired t test. Results: The hypoxic state of a severely damaged muscle increased the proliferation and osteogenic differentiation of mrSCs. mrSCs isolated from damaged muscles also displayed greater sensitivity to osteogenic signals, especially BMP9, than did mrSCs from a healthy muscle. In hypoxic conditions, mrSCs isolated from a control muscle were more proliferative and were more prone to osteogenic differentiation. Interestingly, Smad1/5/8 activation was detected in hypoxic conditions and was still present after 5 days, while Smad1/5/8 phosphorylation could not be detected after 3 h of normoxic incubator condition. BMP9 mRNA transcripts and protein levels were higher in mrSCs cultured in hypoxic conditions. Our results suggest that low-oxygen levels in damaged muscle influence mrSC behavior by facilitating their differentiation into osteoblasts. This effect may be mediated partly through the activation of the Smad pathway and the expression of osteoinductive growth factors such as BMP9 by mrSCs. Conclusion: Hypoxia should be considered a key factor in the microenvironment of damaged muscle that triggers HO.

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Section: Introductionmentioning

confidence: 99%

Muscle injury-induced hypoxia alters the proliferation and differentiation potentials of muscle resident stromal cells

et al. 2019

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“…In traumatic HO, more severe levels of muscular trauma, as in cases of arthroplasty and blast trauma, can lead to an HO incidence of 20% and 64.6%, respectively [6], [7]. Muscle injury usually incurs an inflammatory response, and antiinflammatory drugs have been used as prophylaxis in HO-susceptible patients [8], [9]. However, the precise mechanism by which muscle injury facilitates HO formation and the mechanistic rationale for the use of antiinflammatory drugs in the prevention of HO are still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Muscle injury promotes heterotopic ossification by stimulating local bone morphogenetic protein-7 production

Jiang

Lin

et al. 2019

Journal of Orthopaedic Translation

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Background Heterotopic ossification (HO) is a pathological condition of abnormal bone formation in soft tissue, which causes pain and restricted range of motion in patients. There are two broad categories of HO, hereditary and acquired. Although different types of HO do not use identical mechanistic pathways of pathogenesis, muscle injury appears to be a unifying feature for all types of HO. However, little is known about the mechanisms by which muscle injury facilitates HO formation. Objective and method This study aimed to explore the cellular and molecular mechanisms linking muscle injury to HO by using cardiotoxin to induce muscle injury in a bone morphogenetic protein-2 (BMP-2)–induced HO mouse model. Results We found that muscle injury augmented HO formation and that this effect was correlated with BMP signalling activation and upregulation of BMP-7 expression at the early phase of HO progression. We further demonstrated that inhibition of BMP-7 activity in vitro suppressed the osteogenesis-promoting effect of conditioned medium derived from injured muscle tissue and in vivo reduced the volume of HO formation. We also showed that antiinflammatory drug treatment reduced the volume of HO with concomitant reduction in BMP-7 production. Conclusion In summary, our study has identified BMP-7 as a key osteoinductive factor in injured muscle that facilitates HO formation. The translational potential of this article Our results provide a candidate mechanistic rationale for the use of antiinflammatory drugs in the prevention of HO.

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“…For example, HO is believed to originate from the convergence of multiple mechanisms that closely involve the interaction of the immune system and the central nervous system (Forsberg et al, 2014; Convente et al, 2015; Kraft et al, 2016; Sullivan et al, 2013). More specifically, a growing body of evidence highlights the involvement of the blood-brain-barrier (BBB) in HO formation (Huang et al, 2018). Interestingly, BBB permeability dysfunction is a well-known consequence of TBI and has been identified as a cause for high incidence rates of HO in patients with moderate to severe TBIs (Toffoli et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, concomitant limb fracture and TBI is associated with a twofold increase risk of HO occurrence (Foruria et al, 2014; Dizdar et al, 2013). A possible explanation for the high occurrence of HO in orthopedic patients with a TBI is the overlapping physiopathological mechanisms involved in both injuries, namely dysfunctions in the blood-brain barrier permeability, substance P increase, and prolonged pro-inflammatory cytokine release, making the physiological environment more prone to HO formation (Huang et al, 2018; Evans et al, 2012). These pathological mechanisms are also observed after the mildest form of TBI, the mild TBI (mTBI).…”

Section: Introductionmentioning

confidence: 99%

Investigating the incidence and magnitude of heterotopic ossification with and without joints involvement in patients with a limb fracture and mild traumatic brain injury

et al. 2019

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Objectives This study seeks to evaluate the incidence rate of heterotopic ossification (HO) formation in patients afflicted by an isolated limb fracture (ILF) and a concomitant mild traumatic brain injury (mTBI). Methods The current study is an observational study including ILF patients with or without a concomitant mTBI recruited from an orthopedic clinic of a Level 1 Trauma Hospital. Patients were diagnosed with a mTBI according to the American Congress of Rehabilitation Medicine (ACRM) criteria. Radiographs taken on average 3 months post-trauma were analyzed separately by two distinct specialists for the presence of HO proximally to the fracture site (joints or extra joints). Both raters referred to Brooker's and Della's Valle's classification to establish signs of HO. First, analyses were conducted for the full sample. Secondly, a matched cohort was used in order to control for specific factors, namely age, sex, type of injury, and time elapsed between the accident and the analyzed radiograph. Results The full sample included a total of 183 patients with an ILF (94 females; 47.5 years old), of which 50 had a concomitant mTBI and 133 without. Radiographic evidence of HO was significantly higher in patients with an ILF and a mTBI compared to ILF patients (X 2 = 6.50; p = 0.01). The matched cohort consisted of 94 participants (i.e.; 47 patients from the ILF + mTBI group and 47 patients from the ILF group). Again, ILF + mTBI patients presented significantly higher rates of HO signs in comparison to ILF patients (X 2 = 3.69; p = 0.04). Presence of HO was associated with prolonged delays to return to work (RTW) only in ILF + mTBI patients (F = 4.055; p = 0.05) but not in ILF patients (F = 0.823; p = 0.37). Conclusions Study findings suggest that rates of HO are significantly higher proximally to fracture sites when ILF patients sustain a concomitant mTBI, even after controlling for factors known to influence HO. Moreover, results show that HO is associated with a prolonged RTW only in ILF patients with a concomitant mTBI but not in ILF-only patients. The impact of mTBI on HO formation warrants further attention to detect early signs of HO, to identify shared physiopathological mechanisms and, ultimately, to design targeted therapies.

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Relationship between heterotopic ossification and traumatic brain injury

Cited by 47 publications

References 97 publications

Muscle injury-induced hypoxia alters the proliferation and differentiation potentials of muscle resident stromal cells

Muscle injury-induced hypoxia alters the proliferation and differentiation potentials of muscle resident stromal cells

Muscle injury promotes heterotopic ossification by stimulating local bone morphogenetic protein-7 production

Investigating the incidence and magnitude of heterotopic ossification with and without joints involvement in patients with a limb fracture and mild traumatic brain injury

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