Intraarticular injection of CFA induces nerve sprouting and formation of neuroma-like structures in the periosteum. (A) Schematic of the frontal view of a cross-sectioned mouse knee joint illustrating the periosteal region from which the confocal images were obtained (red square). Representative confocal images of CGRP+ and NF200+ sensory nerve fibers (yellow/orange), TH sympathetic nerve fibers (yellow/orange), and DAPI labeled nuclei (blue) in 20 μm-thick knee sections from 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+, NF200+, and TH+ nerve 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 TH+ nerve fibers have sprouted and have a disorganized appearance as compared with vehicle-injected mice. Furthermore, a formation of neuroma-like structures by NF200+ nerve fibers was seen in the femoral periosteum of the geriatric mice injected with CFA (I).