Burn Injury Enhances Bone Formation in Heterotopic Ossification Model

Peterson, Jonathan; Rosa, Sara De La; Sun, Hongli; Oluwatobi, Eboda; Cilwa, Katherine E.; Donneys, Alexis; Morris, Michael D.; Buchman, Steven R.; Cederna, Paul S.; Krebsbach, Paul H.; Wang, Stewart C.; Lévi, Benjamin

doi:10.1097/sla.0b013e318291da85

Cited by 64 publications

(84 citation statements)

References 36 publications

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“…Recent evidence has shown that the development of HO following burn injury may be reduced in older subjects [37]. This is significant given that it has been documented for several years that the availability and functional activity of MSCs may be reduced with increasing age or passage [38].…”

Section: Mesoderm Mesenchymal Stem Cellsmentioning

confidence: 99%

“…Another novel strategy has been demonstrated in a burn-tenotomy rodent HO model [37] whereby hydrolysis of ATP at the burn site lead to reduced HO formation at a distant site. In addition to revealing a potential therapeutic strategy, this "remote ATP hydrolysis" method provides a further mechanistic insight into the role of phosphorylated SMAD proteins in the development of HO.…”

Section: Treatmentmentioning

confidence: 99%

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Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

et al. 2015

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Section: Mesoderm Mesenchymal Stem Cellsmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

et al. 2015

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“…This process occurs in two separate patient populations: those with severe trauma, including large surface-area burns, musculoskeletal injury, orthopedic operations, and even spinal cord injury; and those with a genetic disease known as fibrodysplasia ossificans progressiva (FOP) (1)(2)(3)(4). FOP is caused by a hyperactivating mutation in the type I bone morphogenetic protein (BMP) receptor ACVR1 (Activin type 1 receptor), and patients with FOP develop ectopic bone lesions in the absence of any substantial trauma.…”

mentioning

confidence: 99%

“…In the burn/tenotomy model, mice undergo Achilles' tendon transection with concomitant partial-thickness dorsal burn injury; HO forms in this model at the tendon transection site (2,3). To study genetic HO, two prominent models have evolved: (i) intramuscular HO through Ad.cre-inducible constitutively active ACVR1 (caACVR1: ACVR1 Q207D) with cardiotoxin injection (1), and (ii) congenital HO in conditional caACVR1 knockin mice [Nfatc1 (nuclear factor of activated T-cells, cytoplasmic 1)-cre/caACVR1 fl/wt ] (6).…”

mentioning

confidence: 99%

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

Agarwal

Loder

Brownley

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Pathologic extraskeletal bone formation, or heterotopic ossification (HO), occurs following mechanical trauma, burns, orthopedic operations, and in patients with hyperactivating mutations of the type I bone morphogenetic protein receptor ACVR1 (Activin type 1 receptor). Extraskeletal bone forms through an endochondral process with a cartilage intermediary prompting the hypothesis that hypoxic signaling present during cartilage formation drives HO development and that HO precursor cells derive from a mesenchymal lineage as defined by Paired related homeobox 1 (Prx). Here we demonstrate that Hypoxia inducible factor-1α (Hif1α), a key mediator of cellular adaptation to hypoxia, is highly expressed and active in three separate mouse models: trauma-induced, genetic, and a hybrid model of genetic and trauma-induced HO. In each of these models, Hif1α expression coincides with the expression of master transcription factor of cartilage, Sox9 [(sex determining region Y)-box 9]. Pharmacologic inhibition of Hif1α using PX-478 or rapamycin significantly decreased or inhibited extraskeletal bone formation. Importantly, de novo soft-tissue HO was eliminated or significantly diminished in treated mice. Lineage-tracing mice demonstrate that cells forming HO belong to the Prx lineage. Burn/tenotomy performed in lineage-specific Hif1α knockout mice (Prx-Cre/Hif1α fl:fl ) resulted in substantially decreased HO, and again lack of de novo soft-tissue HO. Genetic loss of Hif1α in mesenchymal cells marked by Prx-cre prevents the formation of the mesenchymal condensations as shown by routine histology and immunostaining for Sox9 and PDGFRα. Pharmacologic inhibition of Hif1α had a similar effect on mesenchymal condensation development. Our findings indicate that Hif1α represents a promising target to prevent and treat pathologic extraskeletal bone.is the pathologic formation of extraskeletal bone in soft tissues. This process occurs in two separate patient populations: those with severe trauma, including large surface-area burns, musculoskeletal injury, orthopedic operations, and even spinal cord injury; and those with a genetic disease known as fibrodysplasia ossificans progressiva (FOP) (1-4). FOP is caused by a hyperactivating mutation in the type I bone morphogenetic protein (BMP) receptor ACVR1 (Activin type 1 receptor), and patients with FOP develop ectopic bone lesions in the absence of any substantial trauma. The clinical sequela of these pathologic ectopic bone formations, whether in the setting of trauma or genetic mutations, include nonhealing wounds, chronic pain, and joint immobility. In the case of FOP, progressive ossification may lead to death as a result of loss of thoracic cage compliance.Treatment options for HO are limited because bone often recurs following surgical resection, and some patients may have nonresectable HO because of its sensitive location. The risk of an operation may outweigh the benefits of excision, especially in the face of recurrence (5). Therefore, there is a need to identify therapeutic options ...

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“…HO has been reported in at least 50% of patients who have incurred major burn injuries, suggesting that severity and size of injury significantly contribute to the production of HO. Additionally, the ectopic bone can be found distant to the actual burn injury 11. Recent military combat operations have heightened attention to war‐related wounds, 80% of which are caused by high‐energy explosive mechanisms.…”

Section: Trauma Statesmentioning

confidence: 99%