Figure 4

Sensory nerve fiber sprouting and formation of neuroma-like structures in the painful geriatric arthritic knee joint. Schematic of a frontal view of a cross-sectioned mouse knee joint (A). The red square illustrates the synovial region from which the confocal images were obtained. Representative confocal images of calcitonin gene-related peptide (CGRP⁺), neurofilament 200-kDa (NF200⁺) sensory nerve fibers (yellow/orange), and growth-associated protein (GAP43; marker of fibers undergo regeneration, yellow/orange) and DAPI-labeled nuclei (blue) in knee-joint sections (20 μm thick) of vehicle-injected (B, D, F, H) and CFA-injected (C, E, G, I) mice. In vehicle-injected mice, a low-level, regular pattern of innervation by CGRP⁺ and NF200⁺ fibers is observed in the synovial space of the knee joint. Twenty-eight days after the initial CFA injection, a significant number of CGRP⁺, NF200⁺, and GAP43⁺ nerve fibers have sprouted and have a disorganized appearance, as compared with vehicle-injected mice. Note that CGRP⁺, NF200⁺, and GAP43⁺ sprouted nerve fibers are localized in the synovium and are not observed in the meniscus of the joint. Furthermore, formation of neuroma-like structures occurred in the synovium of the geriatric mice injected with CFA (G).