In a rigorously masked, randomized, placebo-controlled trial in client-owned dogs with spontaneous hip or elbow osteoarthritis, subcutaneous EF-M2 produced clinically meaningful improvements in pain and objective locomotor function over four weeks, accompanied by coherent pharmacodynamic shifts toward an M2-dominant serum signature (ARG1/iNOS ↑, IL-10 ↑, TNF-α ↓) and a tolerability profile indistinguishable from placebo—first-in-species evidence that targeted macrophage modulation translates into functional benefit in vivo [15,16]. Here, TNF is linked to osteoarthritis.