Objective To investigate the expression and significance of hypoxia?inducible factor?1α (HIF?1α), OPN, IL?1β, TNF?α, MMP?13, and NGF proteins in SD rats with knee osteoarthritis KOA induced by monosodium and model (KOA) groups. On day 0, the rats were anesthetized with sodium pentobarbital, and 50 μL of normal saline containing 2 mg of MIA was injected into the joint cavity of the KOA group through the infrapatellar ligament of the right knee. In the sham group, 50 μL sterile saline was injected into the knee joint cavity. SD rats were euthanized by overdosed anesthesia on days 0, 3, 7, 10, and 14 after measuring the diameter of the right knee joint and the weight?bearing capacity. Cartilage and synovial tissue were collected. Synovial tissues were primary cultured, and the purity and activity of fibroblast?like synoviocytes (FLSs) were assessed, and FLSs were treated with dexamethasone. Western Blot was used to detect HIF?1α, osteopontin (OPN), interleukin?1β (IL?1β), tumor necrosis factor?α (TNF?α), matrix metalloproteinase?13 (MMP?13), and nerve growth factor (NGF) proteins. Results Compared with the Sham group, HIF?1α, OPN, IL?1β, and TNF?α expression was increased at 3 days after injection of MIA into the knee cavity and showed an increasing trend. The transverse diameter of the knee cavity in the MIA group was significantly larger than that in the Sham group on days 7 and 14 after palpation. On day 3 after injection of MIA into the knee cavity of rats, the weight bearing capacity of the right hind limb continued to be < 26%, which was significantly lower compared with the Sham group. Primary FLSs were successfully isolated by 0.2% type Ⅰ collagenase digestion. After treatment of FLSs from KOA rats with dexamethasone, secretion of proinflammatory factors and expression of MMP?13 and NGF proteins were decreased significantly. Conclusions HIF?1α, OPN, IL?1β, TNF?α, MMP?13, and NGF play major roles in cartilage and synovial inflammation, cartilage degradation, matrix destruction, and joint pain. They are important targets for joint pain management, regulation of inflammatory responses, and inhibition of cartilage degradation and matrix destruction, and the development of novel OA analgesics.