Evaluating the Therapeutic Potential of Bone-Marrow Mesenchymal Stromal Cells and Exercise in a Post-Traumatic Osteoarthritis Model: Functional and Radiographic Analysis

Abstract

Background & Aim The management and optimal treatment of post-traumatic osteoarthritis (PTOA) in the young active patient remains a challenge. Rehabilitation has long been used as a treatment modality for patients with OA in order to improve knee function by decreasing joint pain and stiffness. This study aims to analyze the interaction between bone-marrow mesenchymal stromal cells (BM-MSCs) and exercise as a therapeutic strategy to halt or ameliorate the progression of PTOA in a meniscus destabilization model. Methods, Results & Conclusion 12 week old wild-type C57BL/6 male mice (n=185) underwent destabilization of medial meniscus (DMM) surgery in the right knee. At 3 weeks after surgery, the animals received an intra-articular injection (vehicle or BM-MSCs) and were randomly assigned to their respective activity group (free cage,FC; or treadmill,T). OA development was evaluated using micro-CT, X-Ray and routine histology (OARSI and osteophyte scoring system). Gait analysis was performed and several kinematic parameters were quantified. BM-MSCs adhere to the synovial membrane 24h after injection (Fig1).Histopathologic scores demonstrated cartilage degradation and osteophyte formation beginning at 8w post-DMM predominantly in the treadmill groups. Ectopic bone formation was significantly more prominent in the T+BM-MSCs group at 12w (Fig2). Micro-CT analysis revealed marked anatomical changes in femoral and tibial trabecular and subchondral bone on the medial side, ectopic ossification and osteophyte formation, strongly correlated with the T+BM-MSCs group over time. Gait analysis revealed an antalgic pattern in all groups starting at 4w. Only treadmill injection groups were not significantly different by 12w, suggesting that the combination of injection and exercise ameliorated motion/function. Pain behavior at 12w was lowest in the treadmill groups, with no significant differences between groups or across timepoints. Footprint area and intensity imbalance were significant increased starting at 8w. Significance differences were observed only between the T+BM-MSCs group and FC no injection at 12w (Fig 3). The fate of BM-MSCs injected into an OA joint environment is affected by mechanical loading. Further studies are necessary to understand how the interaction between mechanical and biologic factors influences the biologic responses to implanted cells. Such information will help to identify rehabilitation techniques to aid development of innovative therapies to mitigate or ameliorate the development of PTOA.