Osteoarthritis is the most common joint disorder with aging, but its cause is unknown. Mice lose joint afferents with aging, and this loss precedes development of osteoarthritis. We hypothesized a loss of joint afferents is involved in the pathogenesis of osteoarthritis. To test this hypothesis, we denervated knee joints of 16 rats at age 2 months, by intra-articular injection of an immunotoxin. The immunotoxin killed neurons after retrograde axonal transport to the cell body. At 16 or 24 months follow-up, each joint was histologically assessed and assigned an osteoarthritis score. At follow-up, the number of joint afferents had spontaneously decreased by 42% in control knees and 69% in denervated knees. We found that control knees developed osteoarthritic changes with aging. However, denervated knees had far more severe changes, as evidenced by a 54% higher average osteoarthritis score than control knees (P = 0.0016, both groups 16 knees). These results suggest a loss of afferents predisposes a joint to osteoarthritis. We propose the spontaneous loss of neurons with aging may be a normal developmental process. To explain the mechanism causing osteoarthritis, we suggest denervation permits aberrant joint loading, either by disturbing neuromuscular joint control, or by inducing joint laxity after neurogenic loss of tissue homeostasis.