Intriguingly, the inflammation-associated enhancers including RL-D4, RL-D5, RL-D6, and E3 are located in the intergenic region between RANKL and A-kinase anchoring protein 11, an area that has been expanded during vertebrate evolution.63 We suspect that the emergence of such inflammation-associated RANKL enhancers during evolution may have linked immune activation to osteoclastic bone resorption and thus driven the emergence of inflammatory bone disease, the earliest evidence of which is periodontitis-induced bone damage in a 275 million-year-old terrestrial reptile. The gene discussed is TNFSF11; the disease is bone inflammation disease.