Activation of calcitonin gene-related peptide signaling through the prostaglandin E2-EP1/EP2/EP4 receptor pathway in synovium of knee osteoarthritis patients

Minatani, Atsushi; Uchida, Kentaro; Inoue, Gen; Takano, Shotaro; Aikawa, Jun; Miyagi, Masayuki; Fujimaki, Hisako; Iwase, Dai; Onuma, Kenji; Matsumoto, Toshihide; Takaso, Masashi

doi:10.1186/s13018-016-0460-4

Cited by 29 publications

(50 citation statements)

References 34 publications

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“…Consistent with previous reports [18], CGRP was localized in the synovial lining layer of knee OA patients. CGRP-positive cells were also detected in the capillaries of the IPFP of knee OA patients.…”

Section: Discussionsupporting

confidence: 93%

“…A correlation between CGRP and COX-2 expression levels was previously identified in the synovium of OA patients [18]. In addition, prostaglandin E2 (PGE2), the enzymatic product of COX-2, was shown to stimulate synovial CGRP gene expression [18].…”

Section: Resultsmentioning

confidence: 99%

“…In addition, prostaglandin E2 (PGE2), the enzymatic product of COX-2, was shown to stimulate synovial CGRP gene expression [18]. To investigate the possible regulation of CGRP by COX-2 in IPFP, CGRP and COX-2 expression levels in the IPFP of OA patients were measured (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Expression of calcitonin gene-related peptide in the infrapatellar fat pad in knee osteoarthritis patients

et al. 2017

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BackgroundThe infrapatellar fat pad (IPFP) has been implicated as a possible source of osteoarthritis (OA) development and knee pain due to the production of inflammatory mediators and the existence of nerve fibers within this structure. Calcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide that is localized to joint tissues and has recently been implicated in the development of knee OA and OA pain. To date, however, the expression levels of CGRP in the IPFP of human knee OA patients have not been examined.MethodsIFFP and synovial (SYN) tissues were harvested from 100 individuals with radiographic knee OA (unilateral Kellgren/Lawrence [K/L] grades 2–4) during total knee arthroplasty and subjected to immunohistochemical analysis for CGRP localization. In addition, the messenger RNA (mRNA) expression levels of CGRP and cyclooxygenase-2 (COX-2) in the collected tissues were evaluated and compared using real-time PCR analysis of total RNA extracts. CGRP and COX-2 mRNA expression were also compared among individuals with K/L grades 2–4.ResultsCGRP-positive cells were detected in the capillaries within the IPFP and lining layer of SYN tissue. The expression levels of CGRP in the IPFP were positively correlated with COX-2 and were significantly higher than those in SYN tissue. CGRP expression in tissue from the KL4 group was twofold higher than that from the KL2 group.ConclusionsThe IPFP of knee OA patients produces relatively high levels of CGRP, which may be regulated by COX-2 at the transcriptional level. Further studies are needed to determine if CGRP levels are directly linked to OA pathology.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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Expression of calcitonin gene-related peptide in the infrapatellar fat pad in knee osteoarthritis patients

et al. 2017

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“…CGRP expression is regulated by inflammatory cytokines, growth factors and PGE2 in several cell types, such as immune,15–17 epithelial,18 neural19,20 and synovial cells 6. In a previous study, a correlation between CGRP and COX-2 expression was detected in the synovial tissue of 43 patients, and the enzymatic product of COX-2 (PGE2) also stimulated CGRP gene expression in synovial cell cultures containing fibroblasts and macrophages 6.…”

Section: Discussionmentioning

confidence: 95%

“…Specifically, CGRP was detected in the synovial lining layer of patients with developmental dysplasia of the hip, and it stimulated inflammatory cytokine expression in cultured synoviocytes 5. CGRP expression in synoviocytes from OA patients was increased by prostaglandin E2 (PGE2) 6. In addition to fibroblast -like synoviocytes, the synovial lining layer also contains macrophage-like cells, in which levels of CGRP expression have not been determined.…”

Section: Introductionmentioning

confidence: 99%

Increase and regulation of synovial calcitonin gene-related peptide expression in patients with painful knee osteoarthritis

Takano¹,

Uchida²,

Inoue³

et al. 2017

JPR

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BackgroundRecent studies suggest that the vasodilatory neuropeptide calcitonin gene-related peptide (CGRP) is localized in the synovial tissue and may be involved in the pathology of hip and knee osteoarthritis (OA). However, the regulation and relationship between pain and CGRP expression levels in the synovial tissue of human OA patients are not fully understood.MethodsSynovial tissues were harvested from 74 participants with radiographic knee OA (unilateral Kellgren/Lawrence grades 3–4) during total knee arthroplasty. CGRP-expressing cells in the resected tissue were identified by immunohistochemical analyses. To examine CGRP expression levels, CD14-positive (CD14+) (macrophage-rich cell fraction) and CD14-negative (CD14−; fibroblast-rich cell fraction) cells were isolated from the synovial tissue. To investigate the involvement of prostaglandin E2 (PGE2) in the regulation of CGRP expression, cultured CD14− and CD14+ cells were stimulated with PGE2. In addition, CGRP expression levels in the synovial tissue of OA patients with strong/severe (visual analog scale [VAS]≥6) and mild/moderate pain (VAS<6) were compared.ResultsCGRP-positive cells were detected in the intimal lining layer and comprised both CD14− and CD14+ cells. CGRP expression in non-cultured CD14− fractions was significantly higher than that in CD14+ fractions. The expression levels of CGRP were significantly increased in cultured CD14− cell fractions treated with exogenous PGE2, compared to untreated CD14− cell fractions. In contrast, treatment with PGE2 did not increase CGRP regardless of whether or not CD14+ cells expressed CGRP. Furthermore, CGRP expression in the VAS≥6 group was also significantly higher than that in the VAS<6 group.ConclusionThese findings suggest that CGRP expression in the synovial fibroblasts is regulated by the COX-2/PGE2 pathway and that elevation of synovial CGRP levels may contribute to OA pain.

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Macrophage‐derived inflammatory cytokines regulate growth factors and pain‐related molecules in mice with intervertebral disc injury

Miyagi

Uchida

Takano

et al. 2018

Journal Orthopaedic Research

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Upregulation of inflammatory cytokines and various growth factors is a significant contributor to discogenic low back pain. The aim of this study was to investigate possible regulation of pain-related molecules by macrophages and the role of macrophage-derived molecules in injured intervertebral disc (IVD)s. C57BL/6J mice were used in this study. We characterized the expression profiles of genes for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) in both intact and injured IVDs. We examined whether macrophage depletion, induced by systemic injection of clodronate-laden liposomes, affected the expression of these molecules in injured IVDs. The effect of TNF-alpha on cultured F4/80-CD11b-cells in injured IVDs was investigated. Expression of TNF-alpha and IL-1beta was significantly increased in injured IVDs, but decreased by macrophage depletion. Expression of NGF and VEGF was also significantly increased, but by contrast was not decreased by macrophage depletion. TNF-alpha treatment of F4/80-cells from injured IVDs upregulated NGF, VEGF, cyclooxygenase (COX)-2, and microsomal prostaglandin E synthase-1 (mPGES1). IVD injury upregulated inflammatory cytokines and various growth factors. Macrophages in the injured IVDs produced inflammatory cytokines, but not growth factors. Macrophage-derived inflammatory cytokines regulate growth factors and pain-related molecules. These findings demonstrate further complexity in the pathogenesis of discogenic pain. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

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Activation of calcitonin gene-related peptide signaling through the prostaglandin E2-EP1/EP2/EP4 receptor pathway in synovium of knee osteoarthritis patients

Cited by 29 publications

References 34 publications

Expression of calcitonin gene-related peptide in the infrapatellar fat pad in knee osteoarthritis patients

Expression of calcitonin gene-related peptide in the infrapatellar fat pad in knee osteoarthritis patients

Increase and regulation of synovial calcitonin gene-related peptide expression in patients with painful knee osteoarthritis

Macrophage‐derived inflammatory cytokines regulate growth factors and pain‐related molecules in mice with intervertebral disc injury

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