Non-invasive mouse models of post-traumatic osteoarthritis

Abstract

Animal models of osteoarthritis (OA) are essential tools for investigating the development of the disease on a more rapid timeline than human OA. Mice are particularly useful due to the plethora of genetically modified or inbred mouse strains available. The majority of available mouse models of OA use a joint injury or other acute insult to initiate joint degeneration, representing post-traumatic osteoarthritis (PTOA). However, no consensus exists on which injury methods are most translatable to human OA. Currently, surgical injury methods are most commonly used for studies of OA in mice; however, these methods may have confounding effects due to the surgical/invasive injury procedure itself, rather than the targeted joint injury. Non-invasive injury methods avoid this complication by mechanically inducing a joint injury externally, without breaking the skin or disrupting the joint. In this regard, non-invasive injury models may be crucial for investigating early adaptive processes initiated at the time of injury, and may be more representative of human OA in which injury is induced mechanically. A small number of non-invasive mouse models of PTOA have been described within the last few years, including intra-articular fracture of tibial subchondral bone, cyclic tibial compression loading of articular cartilage, and anterior cruciate ligament (ACL) rupture via tibial compression overload. This review describes the methods used to induce joint injury in each of these non-invasive models, and presents the findings of studies utilizing these models. Altogether, these non-invasive mouse models represent a unique and important spectrum of animal models for studying different aspects of PTOA.

Keywords: Articular cartilage; Knee injury; Mouse model; Post-traumatic osteoarthritis (PTOA).

Figure 1

Conceptual framework of the immediate cellular responses to acute joint trauma. Both catabolic and anabolic processes are involved in the response to the injury, and overlap with one another. Image courtesy of Susanna Chubinskaya. From Anderson et al. [100]. Used with permission.

Figure 2

(A) Alignment of the cradle and indenter for creating a closed articular fracture in the mouse knee. (B–C) Radiographs of clinically observed (B) human tibial plateau fracture and (C) experimentally created mouse tibial plateau fracture. From Furman et al. [67]. Used with permission.

Figure 3

Correlation between liberated surface area and measured energy of fracture for closed articular fracture in the mouse knee. Fracture severity, as measured from the liberated surface area, was well correlated to the energy of fracture, as calculated from the load-displacement data. From Lewis et al. [68]. Used with permission.

Figure 4

Diagrammatic representation of the cyclic tibial compression loading model. (A) Estimated position of the hind limb and loading direction when placed in the loading apparatus. (B) Diagram of a single cycle of applied load, showing hold and peak load magnitudes, rate of load application, and intervening peak and baseline hold times. (C) Diagrammatic representation of the 5 different loading regimens. From Poulet et al. [80]. Used with permission.

Figure 5

Cartilage matrix changes in the tibia after cyclic tibial compression loading. The left tibiae of young and adult mice were loaded (peak loads of 4.5N and 9.0N in adult mice; 9.0N in young mice) for 1, 2, and 6 weeks. The nonloaded contralateral limb at 6 weeks load duration served as control. Safranin O–fast green staining of the medial articular cartilage reveals that damage to the cartilage matrix occurred following mechanical loading in both young and adult mice, and was exacerbated with longer durations and a higher level of loading in adult mice. Bars = 100 μm. From Ko et al. [83]. Used with permission.

Figure 6

Reduction in pericellular aggrecan (ACAN) thickness and in the intensity of extracellular distribution around the cells in the impact area in mouse knee joint cartilage injured by 3N compressive loading. (A) Loss of Safranin O (S.O.) staining in the impact area. (B) Representative images from TUNEL assay combined with immunofluorescence staining for aggrecan. Note the inferior aggrecan encapsulation and thickness around apoptotic chondrocytes (nuclei stained green) in the injured area, compared to clear pericellular aggrecan in TUNEL-negative cells (nuclei stained blue). Bar = 20 μm. From Wu et al. [84]. Used with permission.

Figure 7

Tibial compression overload ACL injury (A) Tibial compression loading caused a transient anterior subluxation of the tibia relative to the distal femur. (B) An anesthetized mouse with the right lower leg in the tibial compression loading system. (C) Knee injury during tibial compression loading was identified by a release of compressive force during the loading cycle, with a continued increase in actuator displacement. From Christiansen et al. [88]. Used with permission.

Figure 8

MicroCT images of injured and uninjured mouse knees 12 weeks after non-invasive ACL injury. Substantial osteophyte formation and joint degeneration were observed in all injured knees. In particular, osteophytes were observed on the anteriomedial aspect of the distal femur, the posteromedial aspect of the proximal tibia, and the medial meniscus. From Lockwood et al. [90]. Used with permission.