Neurovascular plasticity in the knee joint of an arthritic mouse model

Lower numbers of neuropeptide-containing fibers in arthritic joints have be en found as compared to control joints. This may be the result of fiber dep letion, necrosis of fibers, or proliferation of soft, tissues without neura l sprouting. To discriminate between these possibilities, we studied the re lationships between soft tissue proliferation, changes in vascularity of sy novial tissues, and changes in joint innervation during arthritis. Arthritis was induced in the knee joint of mice by a single subpatellar inj ection of methylated bovine serum albumin after previous immunization. Anti bodies to protein gene product 9.5, S-100, and growth-associated protein-43 (GAP-43) were used to study the general innervation pattern. Antibodies to calcitonin gene-related peptide (CGRP), vasointestinal polypeptide (VIP), substance P (SP), and tyrosine hydroxylase (TH) were used to localize senso ry (SP, CGRP, VIP) and sympathetic (TH) fibers. Blood vessels of the joint were studied with ink perfusion, GAP-43, and a vascular marker (LF1). Directly after the induction of arthritis, the synovial cavity was enlarged and filled with leukocytes. From day 4 onward, small sprouting blood vesse ls penetrated the avascular mass of cells in the joint cavity. After 1 week , the vascular sprouting activity and GAP-43 immunoreactivity were maximal, and after 2 weeks, vascular sprouting activity diminished. In the subseque nt period, the synovia slowly regained their prearthritic appearance and th ickness. The most pronounced changes in the general staining pattern of CGRP, SP, VI P, and TH were found in the periosteum. From 2 days to 4 weeks after the in duction of arthritis, the layer of SP, CGRP, and VIP fibers in the femoral periosteum was thicker and more irregular. GAP-43 staining showed many term inal varicosities, which suggested sprouting of nerve fibers. From 2 days t o 2 weeks after the induction of arthritis, the SP and CGRP fibers in the p eriosteum showed gradual depletion. In the thickened subsynovial tissues th at were revascularized, no ingrowth of neural elements was found. As the to tal number of nerve fibers in the synovial tissue did not change, large par ts of the synovia directly facing the joint cavity were not innervated at 1 week after the induction of arthritis. These results strongly suggest that periosteal SP and CGRP fibers were depl eted during arthritis. Synovial proliferation without concomitant fiber gro wth is the main cause of the reduced number of immune cytochemically detect able fibers in the mouse arthritic knee joint. Anat Rec 260:51-61, 2000. (C ) 2000 Wiley-Liss, Inc.