Musculoskeletal changes following non-invasive knee injury using a novel mouse model of post-traumatic osteoarthritis

Christiansen, Blaine A.; Anderson, Matthew; Lee, Cassandra A.; Williams, Jonathan W.; Yik, Jasper H.N.; Haudenschild, Dominik R.

doi:10.1016/j.joca.2012.04.014

Cited by 185 publications

(299 citation statements)

References 22 publications

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“…Additionally, the current study only investigated one time point post-injury. In our previous study we observed differences in bone structure in the affected leg at different time points post-injury [11]. It is therefore possible that bone changes at distant skeletal sites will also be dependent on the time post-injury.…”

Section: Discussionmentioning

confidence: 91%

“…Noninvasive knee injury of mice was performed as previously described [11,12]. Briefly, mice were anesthetized with isoflurane inhalation, and were placed in materials testing system (ELF 3200, Bose, Eden Prairie, MN) with platens designed for tibial compression of mice.…”

Section: Methodsmentioning

confidence: 99%

“…We have developed a noninvasive knee injury model in mice, which uses tibial compression overload to induce ACL injury [11]. The loading rate of this model can be controlled to create ACL injuries via either midsubstance tear or ligament rupture with an associated avulsion bone fracture [12].…”

Section: Introductionmentioning

confidence: 99%

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Trabecular Bone Loss at a Distant Skeletal Site Following Noninvasive Knee Injury in Mice

Christiansen

Emami

Fyhrie

et al. 2015

Journal of Biomechanical Engineering

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Traumatic injuries can have systemic consequences, as the early inflammatory response after trauma can lead to tissue destruction at sites not affected by the initial injury. This systemic catabolism may occur in the skeleton following traumatic injuries such as anterior cruciate ligament (ACL) rupture. However, bone loss following injury at distant, unrelated skeletal sites has not yet been established. In the current study, we utilized a mouse knee injury model to determine whether acute knee injury causes a mechanically significant trabecular bone loss at a distant, unrelated skeletal site (L5 vertebral body). Knee injury was noninvasively induced using either high-speed (HS; 500 mm/s) or lowspeed (LS; 1 mm/s) tibial compression overload. HS injury creates an ACL rupture by midsubstance tear, while LS injury creates an ACL rupture with an associated avulsion bone fracture. At 10 days post-injury, vertebral trabecular bone structure was quantified using high-resolution microcomputed tomography (lCT), and differences in mechanical properties were determined using finite element modeling (FEM) and compressive mechanical testing. We hypothesized that knee injury would initiate a loss of trabecular bone structure and strength at the L5 vertebral body. Consistent with our hypothesis, we found significant decreases in trabecular bone volume fraction (BV/TV) and trabecular number at the L5 vertebral body in LS injured mice compared to sham (À8.8% and À5.0%, respectively), while HS injured mice exhibited a similar, but lower magnitude response (À5.1% and À2.5%, respectively). Contrary to our hypothesis, this decrease in trabecular bone structure did not translate to a significant deficit in compressive stiffness or ultimate load of the full trabecular body assessed by mechanical testing or FEM. However, we were able to detect significant decreases in compressive stiffness in both HS and LS injured specimens when FE models were loaded directly through the trabecular bone region (À9.9% and À8.1%, and 3, respectively). This finding may be particularly important for osteoporotic fracture risk, as damage within vertebral bodies has been shown to initiate within the trabecular bone compartment. Altogether, these data point to a systemic trabecular bone loss as a consequence of fracture or traumatic musculoskeletal injury, which may be an underlying mechanism contributing to increased risk of refracture following an initial injury. This finding may have consequences for treatment of acute musculoskeletal injuries and the prevention of future bone fragility.

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Section: Discussionmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

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Trabecular Bone Loss at a Distant Skeletal Site Following Noninvasive Knee Injury in Mice

Christiansen

Emami

Fyhrie

et al. 2015

Journal of Biomechanical Engineering

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“…Mice were subjected to non-invasive ACL rupture induced by a single overload cycle of tibial compression as previously described [24]. Briefly, mice were anesthetized and placed in a prone position in a materials testing system (Bose ElectroForce 3200, Eden Prairie, MN, USA) with tibial compression loading platens (Fig.…”

Section: Methodsmentioning

confidence: 99%

In vivo fluorescence reflectance imaging of protease activity in a mouse model of post-traumatic osteoarthritis

Satkunananthan

Anderson

Jesus

et al. 2014

Osteoarthritis and Cartilage

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Objective Traumatic joint injuries initiate a surge of inflammatory cytokines and proteases that may contribute to cartilage and subchondral bone degeneration. Detecting these early biological processes in animal models of post-traumatic osteoarthritis (PTOA) typically involves ex vivo analysis of blood serum or synovial fluid biomarkers, or destructive histological analysis of the joint. In this study, we used in vivo fluorescence reflectance imaging (FRI) to quantify protease activity, matrix metalloproteinase (MMP) activity, and Cathepsin K activity in mice following ACL rupture. We hypothesized that these processes would be elevated at early time points following traumatic joint injury (1–14 days), but would return to control levels at later time points (4–8 weeks). Design Mice were injured via tibial compression overload, and FRI imaging was performed at multiple time points from 1–56 days after injury using commercially available activatable fluorescent tracers to quantify protease activity, MMP activity, and cathepsin K activity in injured vs. uninjured knees. PTOA was assessed at 56 days post-injury using micro-computed tomography and whole-joint histology. Results Protease activity, MMP activity, and cathepsin K activity were all significantly increased in injured knees relative to uninjured knees at all time points, peaking at 1–7 days post-injury, then decreasing at later time points while still remaining elevated relative to controls. Conclusions This study establishes FRI imaging as a reliable method for in vivo quantification of early biological processes in a translatable mouse model of PTOA, and provides crucial information about the time course of inflammation and biological activity following joint injury. These data may inform future studies aimed at targeting early inflammation to reduce the development of PTOA.

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“…All mice were randomly divided into five groups, including the control (8 mice), PTKO (16 mice), low dose myrtol-treated (12 mice), medium dose myrtol-treated (12 mice) and high dose myrtol-treated (12 mice) groups. This loading protocol causes alendronate rupture with associated avulsion fracture from the distal femur (14). Mice were anesthetized with intraperitoneal injection of 3% sodium pentobarbital (Sigma-Aldrich, St. Louis, MO, USA).…”

Section: Animalsmentioning

confidence: 99%

Myrtol improves post‑traumatic knee osteoarthritis by regulation of reactive oxygen species, transforming growth factor β1 and apoptosis in a mouse model

Duan

Zhang

et al. 2017

Exp Ther Med

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Abstract. The present study tested whether myrtol improves post-traumatic knee osteoarthritis (PTKO) by regulating the reactive oxygen species (ROS), transforming growth factor β1 (TGF-β1) and apoptosis in a mouse model. PTKO model mice were administered with 150, 300 or 450 mg/kg myrtol for 8 weeks. ELISA analysis was used to measure tumor necrosis factor-α, interleukin-6, malondialdehyde, superoxide dismutase, reactive oxygen species and TGF-β1 levels. Caspase-3 and Bax protein expressions were analyzed using western blot analysis. In the current study, treatment with myrtol improved the tissue damage and osteoarthritis score, while it also reversed the subchondral bone thickness, subchondral bone density, trabecular bone volume/relative trabecular bone volume ratio and trabecular bone spacing in PTKO mice. The activity of tumor necrosis factor α, interleukin-6, TGF-β1, malondialdehyde, superoxide dismutase and ROS were effectively inhibited, and the protein expression of caspase-3 and Bax were clearly suppressed by treatment with myrtol in a mouse model of PTKO. In conclusion, the results demonstrated that myrtol treatment improved PTKO through the suppression of inflammation, oxidative stress, ROS, TGF-β1 and Bax/caspase-3 in mice, and myrtol may be a potential agent for clinical therapy. IntroductionPost-traumatic knee osteoarthritis (PTKO) is a common disease presenting joint degenerative changes (1). PTKO is most frequently detected on the elderly population, with an estimated 15 million cases in China (2). Survey data in the United States also demonstrated that PTKO is the second most common cause of disability in males >50 years old, after cardiovascular disease (3). Thus, prevention and treatment of PTKO have become one of the most difficult issues in clinical practice at present (3).Transforming growth factor β1 (TGF-β1) is a member of the TGF-β superfamily and a type of multifunctional polypeptide growth factor (4). It participates in the proliferation and differentiation processes of diversified cell types, such as chondrocytes, epithelial cells and fibroblasts, and has essential regulating effects in the developing process of embryo, organs and cartilage. Studies have demonstrated that, in the chondrocytes of rabbits and cattle, TGF-β1 can regulate the synthesis of proteoglycan (4,5). In addition, TGF-β1 has the ability to promote synthesis of type II collagen by reducing consumption of proteoglycan in order to repair the cartilage (6). Therefore, it can be seen that TGF-β1 serves an important regulatory role in the process of maintaining chondrocytes and cartilage (7).PTKO is a chronic autoimmune disease characterized by joint synovitis, and its early lesion mainly presents on the synovial membrane (8). Synovial cells are subject to rapid proliferation due to autoimmune response resulting from an external stimulus, such as infection or trauma (9); thus, the infiltration of diversified inflammatory cells on the synovial membrane is enhanced (9). In addition, a large number of cytokines, inflammator...

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Musculoskeletal changes following non-invasive knee injury using a novel mouse model of post-traumatic osteoarthritis

Abstract: This study establishes a novel mouse model of PTOA, and describes the time course of musculoskeletal changes following knee injury, helping to establish the window of opportunity for preventative treatment.

Cited by 185 publications

References 22 publications

Trabecular Bone Loss at a Distant Skeletal Site Following Noninvasive Knee Injury in Mice

Trabecular Bone Loss at a Distant Skeletal Site Following Noninvasive Knee Injury in Mice

In vivo fluorescence reflectance imaging of protease activity in a mouse model of post-traumatic osteoarthritis

Myrtol improves post‑traumatic knee osteoarthritis by regulation of reactive oxygen species, transforming growth factor β1 and apoptosis in a mouse model

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