Targeted genetic deletion of the EP4 receptor gene protects the animals from arthritis-induced histological damage. Representative histological sections (a–d) from diseased EP4^+/+ and EP4^–/– mice demonstrate the significant reduction in damage as shown by safranin O staining (red color signifies proteoglycan presence). Wild-type mice developed severe arthritis with the formation of multiple erosions on the cartilage surface, cellular hyperplasia, and pannus formation. The articular cartilage of EP4^–/– mice was significantly protected from disease. (a) EP4^+/+ stifle joint (2× magnification). (b) EP4^–/– stifle joint (2× magnification). (c) Stifle joint synovial space in an EP4^+/+ animal (10× magnification). (d) Stifle joint synovial space in an EP4^–/– animal (10× magnification). (e and f) Type II collagen neoepitope staining in the stifle synovial joint of EP4^+/+ and EP4^–/– animals, respectively (20× magnification). An increase in staining (EP4^+/+ >> EP4^–/–) correlates with an increase in type II collagen breakdown (EP4^+/+ >> EP4^–/–), a hallmark of arthritis.