Subchondral Bone Disease and Osteoarthritis: Use of Large Animal Models, Novel Techniques, and Emerging Treatments
Development and progression of subchondral bone disease and osteoarthritis involve a combination of biomechanical forces, molecular signaling, and cellular interactions. The following pages explore current understanding of the complex interaction of subchondral bone and articular cartilage. An ovine free fall impact model with direct force acting on a weight-bearing surface with dense sclerotic bone was evaluated as a potential model of joint disease. The impact created focal subchondral bone microdamage with small (mm) full thickness cartilage defects. The method may be beneficial to model post-traumatic osteoarthritis. Additional studies are warranted to further evaluate tissue response to the traumatic injury. A novel method of serial synovial fluid collection using ultrafiltration probes was evaluated in equine metacarpophalangeal joints (n=3). Customized probes with a molecular weight cut-off of 100 kDa were placed and maintained in horses for 72-144 hours with no evidence of lameness at a walk or elevation of pain scores. The probes broke at the glue-membrane interface in 2 horses. While the method was tolerated and effective, additional studies are warranted with different constructs, including the standard probe with a molecular weight cut-off of 30 kDa, for mechanical stability within the joint. An in vitro model of osteoarthritis with synovial fluid-derived mesenchymal stem cells (MSCs) was utilized to evaluate a soluble epoxide hydrolase (sEH) inhibitor as a primer MSCs and treatment of osteoarthritis. Both priming MSCs and treating the MSCs within an inflammatory environment restored viability and activity to non-inflammatory levels. An in vivo 3-way crossover design study with a minimum 2-week washout between treatments was performed in horses with naturally occurring osteoarthritis treated orally with 10 days of 1) sEH inhibitor, 2) cyclooxygenase (COX)-2 selective inhibitor, and 3) sEH inhibitor with half-dose COX-2 selective inhibitor. Gastroscopy and lameness evaluations were performed before and following treatment administration. There was no observed effect of treatments on the gastric environment. Treatments did improve lameness grades, with the combination treatment resulting in persistent improvement 2 weeks after the 10th dose. Soluble epoxide hydrolase inhibitors are a promising new treatment of osteoarthritis that may work synergistically with MSCs and COX inhibitors.