Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification

Yuasa, Masato; Mignemi, Nicholas A.; Nyman, Jeffry S.; Duvall, Craig L.; Schwartz, Herbert S.; Okawa, Atsushi; Yoshii, Toshitaka; Bhattacharjee, Gourab; Zhao, Chenguang; Bible, Jesse E.; Obremskey, William T.; Flick, Matthew J.; Degen, Jay L.; Barnett, Joey V.; Cates, Justin M.; Schoenecker, Jonathan G.

doi:10.1172/jci84059

Cited by 40 publications

(47 citation statements)

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“…While fibrin is not required for bone healing, repair does not properly progress without fibrinolysis. Specifically, the absence of plasminogen results in ectopic ossification and poor healing …”

Section: Inflammatory Phase—inflammatory Cellsmentioning

confidence: 99%

Cellular biology of fracture healing

Bahney

Zondervan²,

Allison³

et al. 2018

Journal Orthopaedic Research

382

353

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The biology of bone healing is a rapidly developing science. Advances in transgenic and gene-targeted mice have enabled tissue and cell-specific investigations of skeletal regeneration. As an example, only recently has it been recognized that chondrocytes convert to osteoblasts during healing bone, and only several years prior, seminal publications reported definitively that the primary tissues contributing bone forming cells during regeneration were the periosteum and endosteum. While genetically modified animals offer incredible insights into the temporal and spatial importance of various gene products, the complexity and rapidity of healing— coupled with the heterogeneity of animal models—renders studies of regenerative biology challenging. Herein, cells that play a key role in bone healing will be reviewed and extracellular mediators regulating their behavior discussed. We will focus on recent studies that explore novel roles of inflammation in bone healing, and the origins and fates of various cells in the fracture environment.

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Section: Inflammatory Phase—inflammatory Cellsmentioning

confidence: 99%

Cellular biology of fracture healing

Bahney

Zondervan²,

Allison³

et al. 2018

Journal Orthopaedic Research

382

353

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“…Prior to the appearance of chondrocytes at the site of injury, vehicle control rats exhibit signs of altered fibrin accumulation as early as 24 h following injury. Fibrin production is necessary to stop hemorrhage following traumatic injury; however hypercoagulability and fibrin accumulation has been associated with neurogenic HO formation and the role of impaired fibrinolysis has been implicated in HO formation . Significantly increased IL‐17 in Palovarotene treated animals at POD‐1 and 3 may induce prostaglandin production which in turn prevents excessive clot formation.…”

Section: Discussionmentioning

confidence: 99%

Palovarotene inhibits connective tissue progenitor cell proliferation in a rat model of combat‐related heterotopic ossification

Wheatley

Cilwa

Dey

et al. 2017

Journal Orthopaedic Research

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Heterotopic ossification (HO) develops in the extremities of wounded service members and is common in the setting of high-energy penetrating injuries and blast-related amputations. No safe and effective prophylaxis modality has been identified for this patient population. Palovarotene has been shown to reduce bone formation in traumatic and genetic models of HO. The purpose of this study was to determine the effects of Palovarotene on inflammation, progenitor cell proliferation, and gene expression following a blast-related amputation in a rodent model (n = 72 animals), as well as the ability of Raman spectroscopy to detect early HO before radiographic changes are present. Treatment with Palovarotene was found to dampen the systemic inflammatory response including the cytokines IL-6 (p = 0.01), TNF-α (p = 0.001), and IFN-γ (p = 0.03) as well as the local inflammatory response via a 76% reduction in the cellular infiltration at post-operative day (POD)-7 (p = 0.03). Palovarotene decreased osteogenic connective tissue progenitor (CTP-O) colonies by as much as 98% both in vitro (p = 0.04) and in vivo (p = 0.01). Palovarotene treated animals exhibited significantly decreased expression of osteo- and chondrogenic genes by POD-7, including BMP4 (p = 0.02). Finally, Raman spectroscopy was able to detect differences between the two groups by POD-1 (p < 0.001). These results indicate that Palovarotene inhibits traumatic HO formation through multiple inter-related mechanisms including anti-inflammatory, anti-proliferative, and gene expression modulation. Further, that Raman spectroscopy is able to detect markers of early HO formation before it becomes radiographically evident, which could facilitate earlier diagnosis and treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1135-1144, 2018.

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“…Male C57BL/6J mice were purchased from Jackson Laboratory and housed at Vanderbilt University in a 12‐h light/dark cycle with food and water provided ad libitum . At 8 weeks of age, an open femur fracture model, previously developed by our lab, was performed. Following adequate anesthesia and analgesia, a 10 to 12 mm long medial incision was made to expose the mid‐shaft of the femur.…”

Section: Methodsmentioning

confidence: 99%

“…Optimal timing for fracture callus chondrocyte graft (FCCG) isolation. Previous longitudinal investigations of fracture callus size and composition have demonstrated (A) maximal soft tissue callus volume at 10 days postfracture (red line) and maximal hard tissue callus between 14 and 21 days postfracture (blue dashed line). (B) at 10 days postinjury, hypertrophic chondrocytes found within the soft tissue callus are producing VEGF‐(A) Top panel: Scale bar = 1 mm.…”

Section: Methodsmentioning

confidence: 99%

Autologous chondrocyte grafting promotes bone formation in the posterolateral spine

et al. 2018

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Background context Pseudarthrosis following spinal fusion remains problematic despite modern surgical and grafting techniques. In surgical spinal fusion, new bone forms via intramembranous and endochondral ossification, with endochondral ossification occurring in the hypoxic zones of the fusion bed. During bone development and fracture healing, the key cellular mediator of endochondral ossification is the hypertrophic chondrocyte given its ability to function in hypoxia and induce neovascularization and ossification. We therefore hypothesize that hypertrophic chondrocytes may be an effective bone graft alternative. Purpose Spinal fusion procedures have increased substantially; yet 5% to 35% of all spinal fusions may result in pseudoarthrosis. Pseudoarthrosis may occur because of implant failure, infection, or biological failure, among other reasons. Advances in surgical techniques and bone grafting have improved fusion; however pseudarthrosis rates remain unacceptably high. Thus, the goal of this study is to investigate hypertrophic chondrocytes as a potential biological graft alternative. Methods Using a validated murine fracture model, hypertrophic chondrocytes were harvested from fracture calluses and transplanted into the posterolateral spines of identical mice. New bone formation was assessed by X‐ray, microcomputed tomography (μCT), and in vivo fluorescent imaging. Results were compared against a standard iliac crest bone graft and a sham surgery control group. Funding for this work was provided by the Department of Orthopaedics and Rehabilitation, the OREF (Grant #16‐150), and The Caitlin Lovejoy Fund. Results Radiography, μCT, and in vivo fluorescent imaging demonstrated that hypertrophic chondrocytes promoted bone formation at rates equivalent to iliac crest autograft. Additionally, μCT analysis demonstrated similar fusion rates in a subset of mice from the iliac crest and hypertrophic chondrocyte groups. Conclusions This proof‐of‐concept study indicates that hypertrophic chondrocytes can promote bone formation comparable to iliac crest bone graft. These findings provide the foundation for future studies to investigate the potential therapeutic use of hypertrophic chondrocytes in spinal fusion.

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Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification

Abstract: A r t i c l e A m e n d m e n t s 3 7 2 3

Cited by 40 publications

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Cellular biology of fracture healing

Cellular biology of fracture healing

Palovarotene inhibits connective tissue progenitor cell proliferation in a rat model of combat‐related heterotopic ossification

Autologous chondrocyte grafting promotes bone formation in the posterolateral spine

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