Comparison of loading rate‐dependent injury modes in a murine model of post‐traumatic osteoarthritis

Lockwood, K. A.; Chu, Bryce T.; Anderson, Matthew; Haudenschild, Dominik R.; Christiansen, Blaine A.

doi:10.1002/jor.22480

Cited by 74 publications

(101 citation statements)

References 25 publications

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“…* p < 0.05 involved either soft tissue damage only (HS injury) or soft tissue damage combined with direct bone damage via avulsion fracture (LS injury). Our previous study using these two injury modes showed that trabecular bone loss in the injured knee at 10 days post-injury is greater for LS injured mice than HS injured mice [12]. The current study showed a similar pattern of trabecular bone loss at a distant, unrelated skeletal site (L5 vertebral body), supporting the conclusion that musculoskeletal injuries that involve bone damage may result in a greater systemic bone loss than injuries involving soft tissue only.…”

Section: Discussionsupporting

confidence: 83%

“…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]. We observed a 20-44% loss of trabecular bone mass in the femoral and tibial epiphysis of the affected limb by 7-14 days post-injury using this model.…”

Section: Introductionmentioning

confidence: 83%

“…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%

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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: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 83%

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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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“…MicroCT analysis of injured and uninjured joints at Day 56 revealed a ~27% loss of trabecular bone volume and notable osteophyte formation in injured joints relative to uninjured joints, consistent with our previous findings [24, 25] (Fig. 6).…”

Section: Resultssupporting

confidence: 92%

“…A single dynamic axial compressive load was applied at 1 mm/s to the right lower leg to a target compressive force of 12 N to produce ACL rupture. This loading protocol produces failure of the ACL with avulsion fracture from the distal femur [24, 25]. Contralateral limbs remained uninjured, and served as internal controls.…”

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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Antibiotic Treatment Prior to Injury Abrogates the Detrimental Effects of LPS in STR/ort Mice Susceptible to Osteoarthritis Development

et al. 2023

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Post traumatic osteoarthritis (PTOA) is a form of secondary osteoarthritis (OA) that develops in ~50% of cases of severe articular joint injuries and leads to chronic and progressive degradation of articular cartilage and other joint tissues. PTOA progression can be exacerbated by repeated injury and systemic inflammation. Few studies have examined approaches for blunting or slowing down PTOA progression with emphasis on systemic inflammation; most arthritis studies focused on the immune system have been in the context of rheumatoid arthritis. To examine how the gut microbiome affects systemic inflammation during PTOA development, we used a chronic antibiotic treatment regimen starting at weaning for 6 weeks before anterior cruciate ligament (ACL) rupture in STR/ort mice combined with lipopolysaccharide (LPS)‐induced systemic inflammation. STR/ort mice develop spontaneous OA as well as a more severe PTOA phenotype than C57Bl/6J mice. By 6 weeks post injury, histological examination showed a more robust cartilage staining in the antibiotic‐treated (AB) STR/ort mice than in the untreated STR/ort controls. Furthermore, we also examined the effects of AB treatment on systemic inflammation and found that the effects of LPS administration before injury are also blunted by AB treatment in STR/ort mice. The AB‐ or AB+LPS‐treated STR/ort injured joints more closely resembled the C57Bl/6J VEH OA phenotypes than the vehicle‐ or LPS‐treated STR/ort, suggesting that antibiotic treatment has the potential to slow disease progression and should be further explored therapeutically as prophylactic post injury. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Comparison of loading rate‐dependent injury modes in a murine model of post‐traumatic osteoarthritis

Cited by 74 publications

References 25 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

Antibiotic Treatment Prior to Injury Abrogates the Detrimental Effects of LPS in STR/ort Mice Susceptible to Osteoarthritis Development

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