This figure illustrates how the knee can engage the nervous system to give rise to different types of pain associated with knee OA. Part 1 shows anterior (1A, 1C) and lateral (1B, 1D) views of the healthy (1A, 1B) and OA knee (1C, 1D). Blue lines emerging from the knee depict nociceptors conveying information from the knee to the CNS (lumbar spinal cord). Green lines depict postganglionic sympathetic fibers sending efferent information from the CNS to the knee. Only sensory fibers are shown in 1a-d. In the OA knee, sensory and sympathetic fibers sprout branches into articular cartilage (* in 1C, 1D). Part 2 illustrates the connection between the knee and the spinal cord. Sensitized afferent fibers can sensitize neurons in the lumbar dorsal horn. This ‘central sensitization’, shown by the red circle in the spinal cord, can become independent of and is modulated differently from ‘peripheral sensitization’. Part 3: Input from nociceptors to the spinal cord is concentrated in the segment associated with the body part the nociceptors innervate (lumbar segments). However, branches of nociceptors also extend to other rostral and caudal segments (blue lines) - normally, nociceptors have minimal impact on neurons in these segments. When nociceptors become sensitized they increase input to the spinal cord and sensitize central neurons in the innervated and uninnervated segments (green lines; red asterisks). Part 4: Multiple intersegmental excitatory and inhibitory spinal connections exist to coordinate nociceptive information (double-arrowed black lines). Central sensitization (red circles) is modulated by this inter-segmental communication. Part 5: Multiple connections exist that ascend from the spinal cord to the brain (blue lines) and descend from the brain to the spinal cord (green lines). Thus, input from the spinal cord engages neurons throughout the brain via complex ascending and descending systems. Input from sensitized spinal neurons can influence activity throughout the neuraxis altering normal processing of nociceptive and non-nociceptive information. Some regions that can be influenced are depicted by red circle. a, meniscus; b, lateral collateral ligament; c, distal femur; d, medial collateral ligament; e, posterior cruciate ligament; f, anterior cruciate ligament; g, proximal tibia; h, synovium; i, periosteum; j, joint capsule; k, patella; l, subchondral bone; m, normal articular cartilage; n, arthritic articular cartilage; o, osteophyte. Figure was adapted from .