title: Sympathetic Neurotransmitters Modulate Osteoclastogenesis and Osteoclast Activity in the Context of Collagen-Induced Arthritis.
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(-6) M 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.
authors.affiliation: Department of Orthopedic Surgery, Experimental Orthopedics, University Hospital Regensburg, Regensburg, Bavaria, Germany; Center for Medical Biotechnology, BioPark I, Regensburg, Bavaria, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Muschter
authors.affiliation: Department of Orthopedic Surgery, Experimental Orthopedics, University Hospital Regensburg, Regensburg, Bavaria, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schäfer
authors.affiliation: Department of Internal Medicine I, Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, University Hospital Regensburg, Regensburg, Bavaria, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Stangl
authors.affiliation: Department of Internal Medicine I, Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, University Hospital Regensburg, Regensburg, Bavaria, Germany.
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Straub
authors.affiliation: Department of Orthopedic Surgery, Experimental Orthopedics, University Hospital Regensburg, Regensburg, Bavaria, Germany; Center for Medical Biotechnology, BioPark I, Regensburg, Bavaria, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Grässel
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology*; D003094:Collagen / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology*; D051381:Rats
chemical_list: D018377:Neurotransmitter Agents; D003094:Collagen