From model to medicine: The horse as a natural and translational model for osteoarthritis drug development

Osteoarthritis is a highly prevalent degenerative joint disease affecting both humans and animals. It is a multifactorial condition involving the entire joint, characterized by inflammation, osteophyte formation, subchondral bone sclerosis, and progressive cartilage degeneration. Clinically, osteoarthritis leads to joint pain and stiffness and represents one of the leading causes of disability worldwide. Although more than 500 million people were affected globally in 2020, and prevalence is expected to nearly double by 2050 due to population aging and increasing obesity, curative treatments remain unavailable. This is largely due to the complex and incompletely understood pathogenesis of the disease. The overarching aim of this thesis was twofold. First, it sought to improve understanding of naturally occurring osteoarthritis in horses, with particular emphasis on disease initiation and early-stage pathology. Second, it investigated two novel therapeutic strategies targeting inflammation and pain associated with osteoarthritis. Using a translational One Medicine approach, horses were selected as a model species because of the strong similarities between equine and human joint pathology and the unmet clinical need in both species. Chapter 2 examined naturally occurring osteoarthritis in semi-wild Konik horses, analyzing age-related changes in cartilage, synovium, synovial fluid, and subchondral bone in three distal forelimb joints. The findings revealed osteoarthritis-related lesions comparable to those seen in domesticated horses and human primary osteoarthritis, though generally less severe, providing a valuable reference baseline. Chapters 3 and 4 used an equine lipopolysaccharide-induced synovitis model in Shetland ponies to evaluate anti-inflammatory effects of liraglutide (a glucagon-like peptide-1 receptor agonist) and analgesic effects of anti-nerve growth factor (NGF) VHH antibodies, respectively. In vitro tests were also performed with liraglutide in equine joint cells. Liraglutide demonstrated anti-inflammatory effects in vitro seen by a reduced production of inflammatory cytokines in chondrocytes and synoviocytes, but limited in vivo efficacy on inflammatory and cartilage metabolism biomarkers in synovial fluid, while anti-NGF VHH significantly reduced lameness shown by objective gait analysis on the treadmill. Overall, this thesis advances understanding of osteoarthritis pathophysiology and highlights promising therapeutic avenues, while underscoring the need for further translational research.