Synovial macrophage-derived IL-1β regulates the calcitonin receptor in osteoarthritic mice

Abstract

SummaryRecent 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. of STR/Ort was higher than that in C57/BL6J mice. Notably, the F4/80 1 cell fraction expressed IL-1b highly, whereas the F4/80 2 cell fraction expressed CGRP, CLR, and RAMP1 highly. In addition, expression of the IL-1b and CLR genes was increased in ST, but was decreased upon macrophage depletion, and the IL-1b treatment of cultured synovial cells up-regulated CLR. Taken together, the present findings suggest that synovial macrophages are the major producers of IL-1b and regulators of CLR in OA mice. Therefore, macrophages and IL-1b may be suitable therapeutic targets for treating OA pain.

Adrenomedullin RegulatesIL-1βGene Expression in F4/80+ Macrophages during Synovial Inflammation

“…In addition, the ST macrophage fraction highly expressed IL-1β , which when exogenously added, stimulated AM expression in synovial cells. These findings are consistent the elevated IL-1 β production previously observed in CD11c + macrophages [16, 21] and the stimulation of AM production by IL-1 β treatment in several cell types, including vascular smooth muscle cells and adipocytes [8, 22]. Taken together, the previous and present findings suggest that activated macrophages contribute to the stimulation of AM production in inflamed joints.…”

Nerve growth factor regulation and production by macrophages in osteoarthritic synovium

“…In addition, STR/Ort mice have higher IL-1b, TNF-a and NGF gene expression in their synovium than C57BL/6J mice [12]. Further, the expression of TNF-a and IL-1b is significantly higher in synovial macrophages compared to fibroblasts [16,17]. Consistent with these findings, we also observed higher expression of TNF-a and IL-1b in macrophages isolated from SYN of knee OA patients.…”

“…Synovial macrophages produce inflammatory cytokines in response to synovial hyperplasia and under OA conditions [12,16,17,23]. Previous studies have also demonstrated an increased number of activated macrophages and IL-1b concentrations in the SYN of a synovial dysplasia mouse model [23].…”

“…OA progression and joint pain are associated with the expression of several proinflammatory cytokines, including IL‐6, IL‐1β and TNF‐α . We have reported previously that TNF‐α and IL‐1β mRNA levels are elevated in the synovial tissue (SYN) of OA model mice, particularly within synovial macrophages .…”

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

“…Macrophage depletion also resulted in decreased production of IL-6, IL-8, MMP-1, and MMP-3 (81). These findings suggest that activation of synovial macrophage is required for the production of MMPs leading to cartilage damage (82)(83)(84)(85). Natural killer cells have also been obtained from synovial tissues of patients undergoing total joint replacements, but the mechanism of pathogenesis has not yet been elucidated in detail (86).…”