In the present study, recombinant substance P with or without LPS was added to rat gingival fibroblasts to observe the expression of HIF-1α, osteoprotegerin (OPG), and receptor activator of NF-kB ligand (RANKL) and the ratio of OPG/RANKL to investigate whether there was a relationships between substance P and HIF-1α in periodontitis. The gene discussed is TNFSF11; the disease is periodontitis.