Abstract
Excessive synovial osteoclastogenesis is a hallmark of rheumatoid arthritis (RA). Concomitantly, local synovial changes comprise neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze if collagen-induced arthritis (CIA) alters bone marrow-derived macrophage (BMM) osteoclastogenesis and osteoclast activity, and how sympathetic neurotransmitters participate in this process. Therefore, BMMs from Dark Agouti rats at different CIA stages were differentiated into osteoclasts in vitro and osteoclast number, cathepsin K activity, matrix resorption and apoptosis were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA) vasoactive intestinal peptide (VIP) and assay-dependent, adenylyl cyclase activator NKH477. We observed modulation of neurotransmitter receptor mRNA expression in CIA osteoclasts without affecting protein level. CIA stage-dependently altered marker gene expression associated with osteoclast differentiation and activity without affecting osteoclast number or activity. Neurotransmitter stimulation modulated osteoclast differentiation, apoptosis and activity. VIP, NA and adenylyl cyclase activator NKH477 inhibited cathepsin K activity and osteoclastogenesis (NKH477, 10-6M NA) whereas ACh mostly acted pro-osteoclastogenic. We conclude that CIA alone does not affect metabolism of in vitro generated osteoclasts whereas stimulation with NA, VIP plus specific activation of adenylyl cyclase induced anti-resorptive effects probably mediated via cAMP signaling. Contrary, we suggest pro-osteoclastogenic and pro-resorptive properties of ACh mediated via muscarinic receptors.
Highlights
One of the most severe characteristics of rheumatoid arthritis (RA) is the destruction of diarthrodial joint bony tissue leading to disability and disuse
20 days p.i. associated with high-grade joint inflammation, mRNA expression of ACh receptors M3 and M5 was significantly upregulated by collagen-induced arthritis (CIA)
Our data suggest that CIA does not affect metabolism and physiology of osteoclasts generated in vitro from bone marrow-derived macrophage (BMM) isolated from arthritic rats
Summary
One of the most severe characteristics of rheumatoid arthritis (RA) is the destruction of diarthrodial joint bony tissue leading to disability and disuse. In vivo studies showed that catecholaminergic noradrenaline (NA) and cholinergic acetylcholine (ACh) / peptidergic vasoactive intestinal peptide (VIP) affect bone homeostasis oppositely. NA signaling preferentially leads to a reduced bone mass phenotype in vivo, either by β2- or by α-adrenoceptor (AR) mediated responses [6,7,8]. In vitro-studies, using murine or human osteoclast-like cells, showed expression of α- and β-adrenoceptor mRNA and enhanced osteoclastogenesis upon βadrenoceptor agonism [9, 10]. In vivo-studies, using VIP self-associated in micelles for nano-medicine application, as well as nicotine and nicotinic α7 ACh receptor agonist ARR–17779, prevented arthritis-induced bone loss [11, 12]. Classical VIP receptor and β2-adrenoceptor signaling is associated with enhanced cyclic AMP levels [15, 16] known to modulate inflammation and initiate predominantly anti-inflammatory mechanisms [17]
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