Catecholaminergic-to-cholinergic transition of sympathetic nerve fibers is stimulated under healthy but not under inflammatory arthritic conditions.
OBJECTIVE
Density of sympathetic nerve fibers decreases in inflamed arthritic tissue tested by immunoreactivity towards tyrosine-hydroxylase (TH, catecholaminergic key enzyme). Since sympathetic nerve fibers may change phenotype from catecholaminergic to cholinergic (example: sweat glands), loss of nerve fibers may relate to undetectable TH. We aimed to investigate possible catecholaminergic-to-cholinergic transition of sympathetic nerve fibers in synovial tissue of animals with arthritis, and patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and we wanted to find a possible transition factor.


METHODS
Nerve fibers were detected by immunofluorescence towards TH (catecholaminergic) and vesicular acetylcholine transporter (cholinergic). Co-culture experiments with sympathetic ganglia and lymphocytes or osteoclast progenitors were designed to find stimulators of catecholaminergic-to-cholinergic transition (including gene expression profiling).


RESULTS
In mouse joints, an increased density of cholinergic relative to catecholaminergic nerve fibers appeared towards day 35 after immunization, but most nerve fibers were located in healthy joint-adjacent skin or muscle and almost none in inflamed synovial tissue. In humans, cholinergic fibers are more prevalent in OA synovial tissue than in RA. Co-culture of sympathetic ganglia with osteoclast progenitors obtained from healthy but not from arthritic animals induced catecholaminergic-to-cholinergic transition. Osteoclast mRNA microarray data indicated that leukemia inhibitory factor (LIF) is a candidate transition factor, which was confirmed in ganglia experiments, particularly, in the presence of progesterone.


CONCLUSIONS
In humans and mice, catecholaminergic-to-cholinergic sympathetic transition happens in less inflamed tissue but not in inflamed arthritic tissue. Under healthy conditions, presence of cholinergic sympathetic nerve fibers may support the cholinergic anti-inflammatory influence recently described.
Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Germany.
Hubert
H
Stangl
Department of Orthopedic Surgery, University Hospital Regensburg, Germany.
Hans-Robert
HR
Springorum
Division of Experimental Orthopedic Surgery, Department of Orthopedic Surgery, University Hospital Regensburg, Germany.
Dominique
D
Muschter
Division of Experimental Orthopedic Surgery, Department of Orthopedic Surgery, University Hospital Regensburg, Germany.
Susanne
S
Grässel
Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Germany. Electronic address: rainer.straub@ukr.de.
Rainer H
RH
Straub
D000109:Acetylcholine / Q000378:metabolism*; D000320:Adrenergic Fibers / Q000378:metabolism*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D010003:Osteoarthritis / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism; D013583:Synovial Membrane
D002395:Catecholamines; D000109:Acetylcholine
Arthritis; Cholinergic sympathetic nerve fiber; Leukemia inhibitory factor; Progesterone; Sympathetic nervous system