A Rat Model of Chondrocyte Death After Closed Intra-Articular Fracture

Swart, Eric; Konopka, Geoffrey; Gardner, Thomas R.; Jane, O; Greisberg, Justin

doi:10.1097/bot.0b013e318251e66d

Cited by 4 publications

(6 citation statements)

References 23 publications

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“…This early up‐regulation of inflammation within the joint may induce catabolic and proinflammatory pathways such as nitric oxide, prostaglandin E 2 , or MMPs and aggrecanases, which are potent extracellular matrix–degrading enzymes. The response to intraarticular fracture observed in the human ankle is consistent with the previously reported response in the mouse knee fracture model and supports the potential use of the preclinical model, or similar models of closed intraarticular fracture , to evaluate therapies to prevent PTA. Characterizing the acute response to intraarticular fracture may provide insight into the role of macrophages, cytokines, and chemokines in the healing process and aid in the understanding of early degenerative changes and the development of PTA.…”

Section: Discussionsupporting

confidence: 85%

Brief Report: Articular Ankle Fracture Results in Increased Synovitis, Synovial Macrophage Infiltration, and Synovial Fluid Concentrations of Inflammatory Cytokines and Chemokines

Furman

Kimmerling

Zura

et al. 2015

Arthritis & Rheumatology

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Objective The inflammatory response following an articular fracture is thought to play a role in the development of posttraumatic arthritis (PTA) but has not been well characterized. The objective of this study was to characterize the acute inflammatory response, both locally and systemically, in joint synovium, synovial fluid (SF), and serum following articular fracture of the ankle. We hypothesized that intraarticular fracture would alter the synovial environment and lead to increased local and systemic inflammation. Methods Synovial tissue biopsy specimens, SF samples, and serum samples were collected from patients with an acute articular ankle fracture (n = 6). Additional samples (normal, ankle osteoarthritis [OA], and knee OA [n = 6 per group]) were included for comparative analyses. Synovial tissue was assessed for synovitis and macrophage count. SF and serum were assessed for cytokines (interferon-γ [IFNγ], interleukin-1β [IL-1β], IL-6, IL-8, IL-10, IL-12p70, and tumor necrosis factor α) and chemokines (eotaxin, eotaxin 3, IFNγ-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], MCP-4, macrophage-derived chemokine, macrophage inflammatory protein 1β, and thymus and activation–regulated chemokine). Results Synovitis scores were significantly higher in ankle fracture tissue compared with normal ankle tissue (P = 0.007), and there was a trend toward an increased abundance of CD68+ macrophages in ankle fracture synovium compared with normal knee synovium (P = 0.06). The concentrations of all cytokines and chemokines were elevated in the SF of patients with ankle fracture compared with those in SF from OA patients with no history of trauma. Only the concentration of IL-6 was significantly increased in the serum of patients with ankle fracture compared with normal serum (P = 0.027). Conclusion Articular fracture of the ankle increased acute local inflammation, as indicated by increased synovitis, increased macrophage infiltration into synovial tissue, and increased SF concentrations of biomarkers of inflammation. Characterizing the acute response to articular fracture provides insight into the healing process and may help to identify patients who may be at greater risk of PTA.

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Section: Discussionsupporting

confidence: 85%

Brief Report: Articular Ankle Fracture Results in Increased Synovitis, Synovial Macrophage Infiltration, and Synovial Fluid Concentrations of Inflammatory Cytokines and Chemokines

Furman

Kimmerling

Zura

et al. 2015

Arthritis & Rheumatology

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“…It is also important to note that the non-surgical aspects of the IAF induction described herein lends itself to further exploration of the early events that might occur following the injury. The work by Swart et al [5] showed the impact of blunt articular impacts on chondrocyte viability increased with time over the first 72 h post-injury. In analogous surgical models, these types of effects might be obscured or unduly confounded by the inflammation and/or tissue damage associated with the surgical procedures required to induce the model.…”

Section: Discussionmentioning

confidence: 99%

“…4 Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, TX, USA. 5 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, USA. 6 Translational Research Program, Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI), Rockville, MD, USA.…”

Section: Supplementary Informationmentioning

confidence: 99%

“…One approach to better recapitulate the effects of high‐energy trauma is through blunt impact loading as is represented by a small number of reports in the literature. Specifically, Seol et al [12] utilized a drop tower in mice finding that impacts on the order of 100 mJ induced subtle osteoarthritic changes characterized by surface and mild proteoglycan depletion, while Swart et al [5] used a similar approach in rats, but focused only on acute outcomes (≤ 72 h) associated with chondrocyte death and did not fully investigate the progression of injury to assess pathological changes; neither of these models reproduced the high‐energy lower extremity trauma (HELET) associated with severe combat‐related (or civilian) injuries. Therefore, an opportunity exists to build upon the prior investigations and develop a non‐invasive rat model of IAF and characterize the degenerative changes associated with PTOA at later time points.…”

Section: Introductionmentioning

confidence: 99%

“…Injuries that penetrate to the subchondral bone (e.g. intra‐articular fractures, IAF) often result in a robust inflammatory response that is associated with fibrocartilage deposition within the osteochondral defects [4, 5]. These sites subsequently result in a high reoccurrence of injury and progressive degeneration through a process termed post‐traumatic osteoarthritis (PTOA).…”

Section: Introductionmentioning

confidence: 99%

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Development and characterization of an intra‐articular fracture mediated model of post‐traumatic osteoarthritis

et al. 2023

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Purpose This study aimed to develop and characterize a closed intra-articular fracture (IAF) mediated post-traumatic osteoarthritis (PTOA) model in rats to serve as a testbed for putative disease modifying interventions. Methods Male rats were subject to a 0 Joule (J), 1 J, 3 J, or 5 J blunt-force impact to the lateral aspect of the knee and allowed to heal for 14 and 56 days. Micro-CT was performed at time of injury and at the specified endpoints to assess bone morphometry and bone mineral density measurements. Cytokines and osteochondral degradation markers were assayed from serum and synovial fluid via immunoassays. Histopathological analyses were performed on decalcified tissues and assessed for evidence of osteochondral degradation. Results High-energy (5 J) blunt impacts consistently induced IAF to the proximal tibia, distal femur, or both while lower energy (1 J and 3 J) impacts did not. CCL2 was found to be elevated in the synovial fluid of rats with IAF at both 14- and 56-days post-injury while COMP and NTX-1 were upregulated chronically relative to sham controls. Histological analysis showed increased immune cell infiltration, increased osteoclasts and osteochondral degradation with IAF relative to sham. Conclusion Based on results from the current study, our data indicates that a 5 J blunt-forced impact adequately and consistently induces hallmark osteoarthritic changes to the articular surface and subchondral bone at 56 days after IAF. Marked development of PTOA pathobiology suggest this model will provide a robust testbed for screening putative disease modifying interventions that might be translated to the clinic for militarily relevant, high-energy joint injuries.

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A New Method for Creating Impact-Induced Intra-Articular Fractures in a Rabbit Model Induces Severe Post-Traumatic Osteoarthritis

Goetz,

Brouillette,

Sakyi

et al. 2024

Journal of Orthopaedic Trauma

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Objectives: The objective of this work was to develop a model of intra-articular fracture in a rabbit and document the speed and severity of degenerative joint changes after fracture fixation. Methods: With IACUC approval, impact-induced intra-articular fractures were created in the distal tibia of 16 New Zealand White rabbits. Fractures were fixed with a plate and screws. Pain and function were monitored at regular postoperative intervals with limb loading analysis. 12 or 26 weeks after fracture, animals were euthanized for histological assessment of cartilage degeneration and micro-CT analysis of bone histomorphometry. Results: Eleven animals successfully completed the study. Maximum foot force in the fractured limb was 41±21% lower than preoperative values (p=0.006) 12 weeks after fracture and remained 25±13% lower (p=0.081) after 26 weeks. Cortical bone mineral density in micro-CT images was 34±13% lower 12 weeks after fracture (p<0.001) and remained (42±8%) lower 26 weeks after fracture (p<0.001). Twelve weeks after fracture, Mankin scores of cartilage degeneration were significantly higher in the medial talus (p=0.007), lateral talus (p<0.001), medial tibia (p=0.017), and lateral tibia (p=0.002) of the fractured limb compared to the uninjured contralateral limb. Average Mankin scores in the talus increased from 12 to 26 weeks (5.9±0.9 to 9.4±0.4; p<0.001 lateral; 5.4±1.8 to 7.8±2.0; p=0.043 medial), indicating substantial and progressive joint degeneration. Conclusions: The ankle joint of the New Zealand White rabbit provides the smallest available model of impact-induced intra-articular fracture that can be treated with clinically relevant techniques and replicates key features of healing and degeneration found in human patients.

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A Rat Model of Chondrocyte Death After Closed Intra-Articular Fracture

Cited by 4 publications

References 23 publications

Brief Report: Articular Ankle Fracture Results in Increased Synovitis, Synovial Macrophage Infiltration, and Synovial Fluid Concentrations of Inflammatory Cytokines and Chemokines

Brief Report: Articular Ankle Fracture Results in Increased Synovitis, Synovial Macrophage Infiltration, and Synovial Fluid Concentrations of Inflammatory Cytokines and Chemokines

Development and characterization of an intra‐articular fracture mediated model of post‐traumatic osteoarthritis

A New Method for Creating Impact-Induced Intra-Articular Fractures in a Rabbit Model Induces Severe Post-Traumatic Osteoarthritis

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