Survey of Animal Models in Post-Traumatic Arthritis: Choosing the Right Model to Answer the Right Question



Fig. 10.1
Summary of outcomes for models of PTA for the mouse, rabbit, and dog. To demonstrate variability in the development of PTA for a small, mid-sized, and large animal model, the primary PTA pathology with the time to development is reported on top and limitations of the model are reported on bottom of outcome boxes. (left) Surgical (open joint) models of PTA can be characterized as joint instability models of arthritis development or articular fracture models that utilize an osteotomy to disrupt the articular surface. (right) Impact or trauma (closed joint) models of PTA can be divided into three categories: models of articular fracture which incorporate fracture induction with impact to the articular surface: models which only impact articular surface and mimic impact associated with soft tissue injuries, like ACL and meniscal tears; and impact, trauma models of ACL tears



Mouse



  • Pros: low cost, availability of genetically modified models or inbred strains, and consistent genetic backgrounds, develop PTA in relatively short time frame.


  • Cons: Small size, limited quantities of tissue and biosample collection, surgical microscope and specialized instruments are often required, surgical variation may be higher between studies, some strains show different background levels of spontaneous OA; lack of consensus in the field as to whether osteoarthritis in the mouse is an appropriate representation of human OA.


Rabbit



  • Pros: relatively low cost, larger joint size, widely reported in literature, form lesions similar to clinically observed chondral defects.


  • Cons: Greater healing capacity relative to human joints, reach skeletal maturity at 10 months; unique gait biomechanics with preferential loading of lateral side of joint, not suitable for exercise studies.


Dog



  • Pros: suitable for longitudinal studies, large joint size, widely reported in literature, trainable for exercise studies, naturally occurring disease populations.


  • Cons: public perception, identified as companion animal, high cost, only limited reagents (e.g., antibodies) available, genetic variability between animals.


To highlight variations in the development of PTA, the specifics of the development of PTA in various joint tissues for the models outlined in the chart are detailed for the mouse, rabbit, and dog in the tables below (Tables 10.1, 10.2, and 10.3).


Table 10.1
Mouse


























































 
Cartilage
Subchondral bone
Synovium

ACL-T [2, 3]
Cartilage lesions in posterior tibia
Subchondral bone erosions of the tibia through to the growth plate at 8 weeks
Increased cellularity and infiltration

ACL-T stab
N/A
N/A
N/A

DMM [3]
Degenerative changes in posterior femur and center of medial tibia; mild at 4 weeks and moderate to severe at 8–12 weeks
Sclerosis at 12 weeks
Moderate synovitis

Meniscal tear
N/A
N/A
N/A

Meniscectomy
N/A
N/A
N/A

Osteotomy
N/A
N/A
N/A

Fx with impact [4, 5]
Moderate to severe degenerative changes at fracture site and all articular surfaces
Sclerosis at 8 weeks
Severe acute synovitis with progression to mild synovitis

Impact only
N/A
N/A
N/A

ACL-T with impact [6]
Degenerative changes in both femoral condyles and medial tibia at 8 weeks
Rapid trabecular bone loss at 7–10 days
Acute synovitis at 7 days



Table 10.2
Dog


























































 
Cartilage
Subchondral bone
Synovium

ACL-T [29–32]
Degeneration in medial compartment at 2 years; thickening at 3 years; focal cartilage loss at 45 months
Early trabecular bone changes at 3–12 weeks
Not reported

ACL-T stab [33–35]
Cartilage erosions at 12 weeks; cartilage thickening observed
Subchondral bone edema in tibia at 6 weeks
Acute synovial inflammation which resolved by 1 week

DMM
N/A
N/A
N/A

Meniscal tear [36–38]
Degenerative changes more prominent on tibial plateau at 1 year
Not reported
Synovitis at 4 weeks

Meniscectomy [39]
Medial side more severe. With partial resection, degenerative changes of tibial plateau at 3 months; with total resection, decrease in mechanical properties at 12 weeks; degenerative changes at 12–24 weeks at sites previously covered by meniscus
With partial resection, sclerosis at 3 months; not reported for full resection
With partial resection, synovial hyperplasia; with total resection of lateral meniscus, no synovitis reported at 3–6 months

Osteotomy
N/A
N/A
N/A

Fx with impact
N/A
N/A
N/A

Impact only (closed joint—patellofemoral) [39– 41]
Moderate loss of GAG staining at 6 weeks; deep clefts and loss of GAG at 6 months
No subchondral bone involvement at 6 weeks; new bone formation at 6 months
Not reported

ACL-T with impact
N/A
N/A
N/A



Table 10.3
Rabbit









































 
Cartilage
Subchondral bone
Synovium

ACL-T [7, 8]
Cartilage lesions at 6–12 weeks
Trabecular bone loss at 4–8 weeks; returned to baseline at 12 weeks
Not reported

ACL-T stab [9]
N/A
N/A
N/A

DMM [10]
Mild degenerative changes on medial tibia and medial femur at 8 weeks
Not reported
Not reported

Meniscal tear [11]
Degenerative changes in tibial plateau at 12 weeks and all surfaces at 9 months with longitudinal medial meniscus tear model
Not reported
Not reported

Meniscectomy [11–14]
Lateral side more severe and rapid degeneration with gross articular lesions at 3 weeks; medial side shows degeneration of tibial plateau at 8 weeks and posterior femoral condyles at 6–9 months
With partial resection, sclerosis of medial tibial plateau reported at 12 weeks; not reported for total resection
Not reported for partial resection; with total resection, synovitis at 2 weeks and fibrotic synovium at 12 weeks

Osteotomy [15–18]
Fibrocartilage and mild fibrillation with larger incongruity; successfully healed defects 2× cartilage thickness

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Nov 27, 2016 | Posted by in RHEUMATOLOGY | Comments Off on Survey of Animal Models in Post-Traumatic Arthritis: Choosing the Right Model to Answer the Right Question

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