title: Synovial macrophage-derived IL-1β regulates the calcitonin receptor in osteoarthritic mice.
abstract: Recent studies have reported that calcitonin gene-related peptide (CGRP) contributes to joint pain. However, regulation of the CGRP/CGRP receptor signalling in osteoarthritis (OA) is not fully understood. To investigate the regulation of CGRP/CGRP receptor signalling by macrophages in the synovial tissue (ST) of OA joints, we characterized the gene expression profiles of CGRP and CGRP receptors in the ST of OA mice (STR/Ort). In addition, we examined whether macrophage depletion by the systemic injection of clodronate-laden liposomes affected the expression of CGRP and CGRP receptors in ST. CD11c(+) macrophages in the ST of STR/Ort and C57BL/6J mice were analysed by flow cytometry. Real-time polymerase chain reaction (PCR) was used to evaluate the expression of interleukin (IL)-1β, CGRP, calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in F4/80(+) and F4/80(-) cells. The effects of IL-1β on the expression of CGRP and CLR by cultured synovial cells were also examined. The percentage of CD11c(+) macrophages in the ST of STR/Ort was higher than that in C57/BL6J mice. Notably, the F4/80(+) cell fraction expressed IL-1β highly, whereas the F4/80(-) cell fraction expressed CGRP, CLR, and RAMP1 highly. In addition, expression of the IL-1β and CLR genes was increased in ST, but was decreased upon macrophage depletion, and the IL-1β treatment of cultured synovial cells up-regulated CLR. Taken together, the present findings suggest that synovial macrophages are the major producers of IL-1β and regulators of CLR in OA mice. Therefore, macrophages and IL-1β may be suitable therapeutic targets for treating OA pain.
authors.affiliation: Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Takano
authors.affiliation: Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Miyagi
authors.affiliation: Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Inoue
authors.affiliation: Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Aikawa
authors.affiliation: Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Fujimaki
authors.affiliation: Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Minatani
authors.affiliation: Department of Immunology, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Immunology, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Iwabuchi
authors.affiliation: Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takaso
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000008:administration & dosage; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000276:immunology*; D058262:Receptor Activity-Modifying Protein 1 / Q000235:genetics / Q000378:metabolism*; D018003:Receptors, Calcitonin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000276:immunology
chemical_list: D000943:Antigens, Differentiation; D058286:Calcitonin Receptor-Like Protein; D053583:Interleukin-1beta; C545505:Ramp1 protein, mouse; D058262:Receptor Activity-Modifying Protein 1; D018003:Receptors, Calcitonin; C036763:monocyte-macrophage differentiation antigen; D004002:Clodronic Acid; D015740:Calcitonin Gene-Related Peptide
keywords: calcitonin receptor; interleukin 1β; osteoarthritis