Background/Purpose: Sympathetic nerve fibers play an important role in bone and tissue homeostasis of joints. However sympathetic nerve fibers are able to switch their phenotype and respective neurotransmitter machinery from sympathetic to cholinergic. This transition was shown in developing sweat glands, in the periosteum and in failing heart tissue. This is crucial since strong anti-inflammatory effects have been described for the α7nicotinic acetylcholine receptor as well as for the cholinergic co-transmitter vasoactive intestinal peptide (VIP). We studied connective tissue obtained from the knee and finger joints of osteoarthritis (OA) and rheumatoid arthritis (RA) patients and tested possible transition requirements in an in-vitro model with murine sympathetic ganglia.

Methods: Knee synovial tissue samples obtained from 44 OA and 21 RA patients and connective as well as bone tissue samples from interphalangeal finger joints obtained from seven OA and five RA patients were stained for tyrosine hydroxylase (TH, noradrenergic fibers), vesicular acetylcholine transporter (VAChT, cholinergic fibers) and VIP (cholinergic fibers). Sympathetic ganglia were obtained from newborn C57Bl/6 mice and double-stained for TH and VAChT after a co-culture period of two days with osteoclast progenitors attained from the femoral and tibial bone marrow from adult healthy and arthritic mice. Supernatants from osteoclast progenitors were tested for possible transition factors. Whole RNA isolated from the respective osteoclast progenitors was screened via microarray analysis in order to identify possible candidate transition factors.

Results: In connective tissue sections from human finger joints, VAChT but not VIP positive cholinergic nerve fibers were more present in OA than in RA patients. In knee synovial tissue no significant difference in the appearance of cholinergic (VAChT and VIP) nerve fibers was found. The ratio of VAChT/TH immunoreactivity of sympathetic ganglia in coculture with osteoclast progenitors from healthy mice was elevated compared to experiments with osteoclast progenitors from arthritic mice. Leukemia inhibitory factor (LIF), a known transition factor from the glycoprotein 130 cytokine family, is present in low concentrations in supernatants from osteoclast progenitor cells but did not induce transition.  Microarray analysis showed an upregulation of several candidate molecules (biglycan, fibronectin, LIF, periostin, tenascin-C, tensin-1, TIMP-1) in the transcriptome of osteoclast progenitors from healthy mice compared to arthritic (n=3 vs. 3, mean fold chance >2.0, p<0.01).

Conclusion: In humans and mice, catecholaminergic-to-cholinergic transition is possible in less inflamed tissue of the joint but not in highly inflamed arthritic tissue.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/catecholaminergic-to-cholinergic-transition-of-sympathetic-nerve-fibers-in-arthritis-and-in-a-co-culture-system-of-sympathetic-ganglia-in-vitro/