R399E, A Mutated Form of Growth and Differentiation Factor 5, for Disease Modification of Osteoarthritis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2023-03, Vol.75 (3), p.375-386
• Main Authors: Gigout, Anne, Werkmann, Daniela, Menges, Stephanie, Brenneis, Christian, Henson, Frances, Cowan, Kyra J., Musil, Djordje, Thudium, Christian S., Gühring, Hans, Michaelis, Martin, Kleinschmidt‐Doerr, Kerstin
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Anterior cruciate ligament; Anterior Cruciate Ligament - metabolism; Anterior Cruciate Ligament - pathology; Anterior Cruciate Ligament - surgery; Anti-inflammatory agents; Arthralgia; Arthritis; Cartilage; Cartilage diseases; Cartilage, Articular - pathology; Cell Differentiation; Cell proliferation; Chondrocytes; Confidence intervals; Differentiation; Evaluation; Factor V - metabolism; Factor V - therapeutic use; Interleukin 6; Interleukins; Joints (anatomy); Menisci; Meniscus; Osteoarthritis; Osteoarthritis - metabolism; Pain; Prostaglandin E2; Rabbits; Sheep; Statistical analysis; Surface structure; Synovium
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.42343

Objective To preclinically characterize a mutant form of growth and differentiation factor 5, R399E, with reduced osteogenic properties as a potential disease‐modifying osteoarthritis (OA) drug. Methods Cartilage, synovium, and meniscus samples from patients with OA were used to evaluate anabolic and antiinflammatory properties of R399E. In the rabbit joint instability model, 65 rabbits underwent transection of the anterior cruciate ligament plus partial meniscectomy. Three intraarticular (IA) R399E doses were administered biweekly 6 times, and static incapacitance was determined to assess joint pain. OA was evaluated 13 weeks after surgery. In sheep, medial meniscus transection was performed to induce OA, dynamic weight bearing was measured in‐life, and OA was assessed after 13 weeks. Results Intermittent exposure to R399E (1 week per month) was sufficient to induce cell proliferation and release of anabolic markers in 3‐dimensional chondrocyte cultures. R399E also inhibited the release of interleukin‐1β (IL‐1β), IL‐6, and prostaglandin E2 from cartilage with synovium, meniscal cell, and synoviocyte cultures. In rabbits, the mean difference (95% confidence interval [95% CI]) in weight bearing for R399E compared to vehicle was −5.8 (95% confidence interval [95% CI] −9.54, −2.15), −7.2 (95% CI −10.93, −3.54), and −7.7 (95% CI −11.49, −3.84) for the 0.6, 6, and 60 μg doses, respectively, 6 hours after the first IA injection, and was statistically significant through the entire study for all doses. Cartilage surface structure improved with the 6‐μg dose. Structural and symptomatic improvement with the same dose was confirmed in the sheep model of OA. Conclusion R399E influences several pathologic processes contributing to OA, highlighting its potential as a disease‐modifying therapy.