A combined model of destabilisation of the medial meniscus and cartilage damage accelerates osteophytogenesis in osteoarthritis

PurposeInjuries involving damage to the articular cartilage can be both physically limiting and painful. Articular cartilage injuries can result from an isolated injury, or in combination with other joint damage. Cartilage has a poor intrinsic regenerative capability, and therefore once damaged, presents a major clinical challenge. Joint injury is known to be a well-established precursor for the development of the osteoarthritis (OA). Pain is one of the most common, and arguably physically limiting, symptoms of OA. However, the origin of pain in OA is poorly understood. Several murine models have been used to study OA (e.g. destabilisation of the medial meniscus (DMM) and anterior cruciate ligament transection (ACLT)). However neither of these models combines simultaneous cartilage injury with joint destabilisation. Therefore, the principle aim of this study was to investigate if the combination of cartilage damage and DMM accelerates the onset of OA-like symptoms when compared with DMM and cartilage damage alone.
MethodsThree models of OA-like joint instability and damage were induced in wild-type (WT) mice. For biomechanical instability, DMM surgery induced medial compartment OA following transection of the medial meniscotibial ligament. For cartilage damage, a micro precision blade was used to make controlled “scratches” (Scratch model) on the cartilage of the tibia under the femoral medial condyle. To combine biomechanical instability with cartilage damage, both DMM and cartilage scratch (Combined model) was performed. Microcomputered tomography (μCT) was used to monitor bone changes, and as an indirect measurement of pain, dynamic weight bearing was assessed in mice 14 days after surgery.
ResultsAt 14 days post-surgery, osteophytes are present in all 3 groups. However, between groups, osteophytes differed in number, appearance, and bone volume. In DMM, 6/8 mice developed protruding osteophytes with an arboreal structure (the initial phase of osteophyte formation). Osteophytes were present in all mice undergoing cartilage scratch surgery, however, they had a larger more calcified appearance, suggesting cartilage could play a role in the acceleration of OA osteophyte pathology. 8/8 WT mice in the Combined model were observed to exhibit 2 or more large, protruding, calcified osteophytes. Osteophytes observed in this Combined model encompassed a larger area of the subchondral bone when compared with DMM or Scratch model alone (14.12 ± 0.31 versus 12.4 ± 0.62, 12.68 ± 0.54, p<0.01). Compared to the osteophytes in the DMM model, it is clear that addition of cartilage damage accelerates the calcification of osteophytes. μCT analysis of the subchondral bone shows both DMM, and Combined models have an increase in subchondral osteosclerosis compared to cartilage damage alone. Further, analysis of subchondral trabecular bone in the Combined model exhibited a significantly higher bone volume over tissue volume compared with the other models used in this study (p=0.0017, two-way ANOVA).Using dynamic weight bearing 14 days post-surgery to assess OA-related pain, we found the Combined model group have a significant increase in load on their front paws when compared with the other 2 groups, suggesting an increase in OA-like pain. 
ConclusionOA is a multi-factorial disease encompassing various different tissues within the joint. Accordingly, a Combined model of OA as presented here allows a more accurate representation of human OA. This study concludes that combining DMM with cartilage damage provides a more robust and reproducible model for OA due to the increased osteophytogenesis. This model also incorporates OA-related pain, which is arguably one of the most problematic and physically limiting symptoms of OA.