Treatment of heterotopic ossification through remote ATP hydrolysis

Peterson, Jonathan; Rosa, Sara De La; Oluwatobi, Eboda; Cilwa, Katherine E.; Agarwal, Shailesh; Buchman, Steven R.; Cederna, Paul S.; Xi, Chuanwu; Morris, Michael D.; Herndon, David N.; Xiao, Wenzhong; Tompkins, Ronald G.; Krebsbach, Paul H.; Wang, Stewart C.; Lévi, Benjamin

doi:10.1126/scitranslmed.3008810

Cited by 118 publications

(143 citation statements)

References 33 publications

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“…Mesenchymal cells with the capacity for osteogenic differentiation and which may serve as HO progenitor cells reside within adipose tissues, making this an appropriate tissue type to assay. Additionally, burn patients are a critical patient population at risk for trauma-induced HO development (2,3,20). Our recent analysis has shown that patients with burn total body surface area (TBSA) > 30% have 23-times higher odds of developing HO compared with patients with smaller surface-area burns, validating use of this cohort of patients with >20% TBSA burns for transcriptome analysis (21).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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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).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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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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186

223

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“…Recently, Peterson et al [19] demonstrated in a murine Achilles tenotomy plus partial-thickness dorsum burn injury model that injured mice develop endochondral ectopic bone and functional joint contractures through BMP-mediated canonical small ''mothers against'' decapentaplegic (SMAD) signaling. Moreover, they report that these orthopaedic disease processes can be attenuated/modulated by targeting adenosine triphosphate (ATP) hydrolysis and SMAD1/5/8 phosphorylation at the burn site using apyrase [19].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, they report that these orthopaedic disease processes can be attenuated/modulated by targeting adenosine triphosphate (ATP) hydrolysis and SMAD1/5/8 phosphorylation at the burn site using apyrase [19]. Interestingly, it has been reported that focused extracorporeal shockwave therapy (ESWT; low-density shockwaves administered orders of magnitude below blast overpressure conditions used in the study) has been shown to induce osteogenic differentiation of marrow-derived mesenchymal stem cells through ATP release and downstream transcriptional signaling events resulting in activation of P2X7 receptors [28].…”

Section: Discussionmentioning

confidence: 99%

Early Characterization of Blast-related Heterotopic Ossification in a Rat Model

Qureshi

Crump

Pavey

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Heterotopic ossification (HO) affects the majority of combat-related lower extremity wounds involving severe fracture and amputation. Defining the timing of early osteogenic-related genes may help identify candidate prophylactic agents and guide the timing of prophylactic therapy after blast and other combat-related extremity injuries. Questions/purposes Using a recently developed animal model of combat-related HO, we sought to determine (1) the timing of early chondrogenesis, cartilage formation, and radiographic ectopic bone development; and (2) the early cartilage and bone-related gene and protein patterns in traumatized soft tissue. Methods We used an established rat HO model consisting of blast exposure, controlled femur fracture, crush injury, and transfemoral amputation through the zone of injury. Postoperatively, rats were euthanized on Days 3 to 28. We assessed evidence of early ectopic bone formation by micro-CT and histology and performed proteomic and gene expression analysis. Results All rats showed radiographic evidence of HO within 28 days. Key chondrogenic (collagen type I alpha 1 [COL1a1], p = 0.016) and osteogenic-related genes (RuntThis work was supported by CDMRP (W81XWH-14-2-0010; PI-JAF) and BUMED (602115HP.3720.001.A1014; PI-JAF). Some of the authors are employees of the US Government. This work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that ''Copyright protection under this title is not available for any work of the United States Government.'' Title 17 U.S.C. §101 defined a US Government work as a work prepared by a military service member or employees of the US Government as part of that person's official duties. The opinions or assertions contained in this paper are the private views of the authors and are not to be construed as reflecting the views, policy or positions of the Department of the Navy, Department of Defense nor the US Government. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research 1 editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research 1 neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA-approval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research. This work performed at the Naval Medical Research Center, Silver Spring, MD, USA. Conclusions We found that genes that regulate early chondrogenic and osteogenic signaling and bone development (COL1a1, RUNX-2, OCN, PHEX, and POU5F1) are induced early during the tissue reparative/healing phase in a rat model simulating a combat-related extremity injury. Clinical Relevance The ability to correlate molecular events with histologic and morphologic changes will assist re...

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Bedside, Benchtop, and Bioengineering: Physicochemical Imaging Techniques in Biomineralization

Eisenstein

Cox

Williams

et al. 2016

Adv Healthcare Materials

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The need to quantify physicochemical properties of mineralization spans many fields. Clinicians, mineralization researchers, and bone tissue bioengineers need to be able to measure the distribution, quantity, and the mechanical and chemical properties of mineralization within a wide variety of substrates from injured muscle to electrospun polymer scaffolds and everything in between. The techniques available to measure these properties are highly diverse in terms of their complexity and utility. Therefore it is of the utmost importance that those who intend to use them have a clear understanding of the advantages and disadvantages of each technique and its appropriateness to their specific application. This review provides all of this information for each technique and uses heterotopic ossification and engineered bone substitutes as examples to illustrate how these techniques have been applied. In addition, we provide novel data using advanced techniques to analyze human samples of combat related heterotopic ossification.

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Treatment of heterotopic ossification through remote ATP hydrolysis

Cited by 118 publications

References 33 publications

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

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

Early Characterization of Blast-related Heterotopic Ossification in a Rat Model

Bedside, Benchtop, and Bioengineering: Physicochemical Imaging Techniques in Biomineralization

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