Osteoarthritis is a degenerative disease marked by articular cartilage degradation, osteophyte hyperplasia, subchondral bone remodeling, and synovial inflammation, primarily manifesting as pain. Notably, normal articular cartilage is devoid of nerve innervation; however, as osteoarthritis advances, innervation emerges in previously uninnervated regions. Axon guidance cues serve as pivotal regulators of nociceptive nerve growth, playing a dual role. On one hand, nerve innervation facilitates injury repair, subchondral bone remodeling, and mitigatessynovial inflammation. Conversely, it heightens pain sensitivity or exacerbates pain symptoms. This intricate interplay is orchestrated by four primary axon guidance cues: netrin-1, slit guidance ligand(SLIT), Eph receptor-interacting proteins (ephrin), and semaphorin3A (Sema3A). This review delved into the intricate role of these cues in the progression of osteoarthritis and elucidates the mechanisms underlying nerve innervation in areas previously lacking innervation.