Increased Intercellular Communication through Gap Junctions May Contribute to Progression of Osteoarthritis

Marino, Andrew A.; Waddell, David D.; Kolomytkin, Oleg V.; Meek, William D.; Wolf, Robert; Sadasivan, Kalia K.; Albright, James A.

doi:10.1097/01.blo.0000129346.29945.3b

Cited by 41 publications

(39 citation statements)

References 26 publications

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“…Cell-to-cell coupling through gap junctions support the formation of complex cellular networks that favor the intercellular exchange of nutrients and second messengers (D’Andrea, Calabrese et al 1998). Gap junctions are present in the synovium (Kolomytkin, Marino et al 2000), and have been shown to affect increased production of matrix metalloproteinases by FLS subjected to pro-inflammatory cytokines (Kolomytkin, Marino et al 2002, Marino, Waddell et al 2004) as well as constitutively in clinical OA samples (Marino, Waddell et al 2004). …”

Section: Discussionmentioning

confidence: 99%

Fibroblast-like synoviocyte mechanosensitivity to fluid shear is modulated by interleukin-1α

Estell

Murphy

Silverstein

et al. 2017

Journal of Biomechanics

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Fibroblast-like synoviocytes (FLS) reside in the synovial membrane of diarthrodial joints and are exposed to a dynamic fluid environment that presents both physical and chemical stimuli. The ability of FLS to sense and respond to these stimuli plays a key role in their normal function, and is implicated in the alterations to function that occur in osteoarthritis (OA). The present work characterizes the response of FLS to fluid flow-induced shear stress via real-time calcium imaging, and tests the hypothesis that this response is modulated by interleukin-1α (IL-1α), a cytokine elevated in OA. FLS demonstrated a robust calcium signaling response to fluid shear that was dose dependent upon stress level and required both external and internal calcium sources. Preconditioning with 10 ng/mL IL-1α for 24 hrs heightened this shear stress response by significantly increasing the percent of responding cells and peak magnitude, while significantly decreasing the time for a peak to occur. Intercellular communication via gap junctions was found to account for a portion of the FLS population response in normal conditions, and was significantly increased by IL-1α preconditioning. IL-1α was also found to significantly increase average length and incidence of the primary cilia, an organelle commonly implicated in shear mechanosensing. These findings suggest that the elevated levels of IL-1α found in the OA environment heighten FLS sensitivity to fluid shear by altering both intercellular communication and individual cell sensitivity, which could affect downstream functions and contribute to progression of the disease state.

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Section: Discussionmentioning

confidence: 99%

Fibroblast-like synoviocyte mechanosensitivity to fluid shear is modulated by interleukin-1α

Estell

Murphy

Silverstein

et al. 2017

Journal of Biomechanics

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“…30 Several studies have implicated Cx43 in the etiology of OA. 19,25,49,50 Synovial biopsies from patients with OA were shown to have an increase in Cx43 expression and an increase in the size and number of gap junction plaques. 25 Ex vivo analysis of these cells revealed that pharmacological inhibition of Cx43 function could reduce the basal and IL-1β-stimulated production of collagenase activity.…”

Section: Introductionmentioning

confidence: 99%

“…19,25,49,50 Synovial biopsies from patients with OA were shown to have an increase in Cx43 expression and an increase in the size and number of gap junction plaques. 25 Ex vivo analysis of these cells revealed that pharmacological inhibition of Cx43 function could reduce the basal and IL-1β-stimulated production of collagenase activity. 19,25 Additionally, the inflammatory cytokine IL-1β has been shown to increase the expression of Cx43 in articular chondrocytes 49,50 and synovial fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

“…25 Ex vivo analysis of these cells revealed that pharmacological inhibition of Cx43 function could reduce the basal and IL-1β-stimulated production of collagenase activity. 19,25 Additionally, the inflammatory cytokine IL-1β has been shown to increase the expression of Cx43 in articular chondrocytes 49,50 and synovial fibroblasts. 34 Recently, a study by Mayan et al 30 investigated cartilage from osteoarthritic knees and femoral heads and found significantly elevated levels of Cx43 compared with non-osteoarthritic cartilage.…”

Section: Introductionmentioning

confidence: 99%

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Identification of shoulder osteoarthritis biomarkers: comparison between shoulders with and without osteoarthritis

Casagrande

Stains

Murthi

2015

Journal of Shoulder and Elbow Surgery

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Background The biological factors associated with shoulder osteoarthritis (OA) have not been elucidated. The purpose of this study was to investigate putative osteoarthritic biomarkers of the shoulder. To our knowledge, this is the first study to analyze shoulder cartilage for OA-associated genes and examine human shoulder cartilage for a novel biomarker, connexin 43 (Cx43). Materials and methods Cartilage from 16 osteoarthritic and 10 non-osteoarthritic humeral heads was assessed for expression of the following genes via real-time polymerase chain reaction: types I, II, and X collagen, metalloproteinases (MMP), tissue inhibitors of MMP (TIMP), interleukins, versican, cyclooxygenase-2 (Cox-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNFα), aggrecanase-2 (ADAMTS5), and Cx43. Results In osteoarthritic shoulders, gene expression of Cx43, ADAMTS5, collagen type I, Cox-2, versican, and TIMP-3 showed predominance (85-, 33-, 13-, 12-, 11.5-, and 3-fold increases, respectively) relative to non-osteoarthritic controls. Spearman correlation analysis showed significant correlations between Cx43 and collagen types I, II, and X, MMP-9, TIMP-2 and -3, versican, Cox-2, iNOS, and ADAMTS5. In osteoarthritic shoulders, Cx43, Cox-2, versican, collagen type I, ADAMTS5, MMP3, and TNFα expressions were significantly increased compared with controls. TIMP-3 and iNOS trended toward significance, with robust expression in osteoarthritic shoulders and low expression in non-osteoarthritic shoulders. Conclusions Certain genes are markedly up-regulated in osteoarthritic shoulders compared with non-osteoarthritic shoulders, with Cx43, Cox-2, versican, collagen type I, ADAMTS5, MMP3, and TNFα expression being significantly increased. These genes might be useful biomarkers for examining shoulder OA.

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“…Synovial cells are connected to each other by an extensive networks of gap junctions, and it may mediate some cellular processes [12,13]. Kolomytkin Marino et al reported that increased ICJP may contribute to the progression of osteoarthritis [15]. The synovial lining cells from patients with osteoarthritis (OA) produced MMP constitutively and in response to stimulation by IL-1β.…”

Section: Discussionmentioning

confidence: 99%

Experimental immunology Tumor necrosis factor-α and matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue is inhibited by blocking gap junction communication

Nanke¹,

Kobashigawa²,

Yago³

et al. 2012

cejoi

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Objective: Our aim was to establish the existence of intercellular communication through gap junctions (ICGJ) in synovial tissues and to show that gap junction communications in synovial tissue plays a role in the pathogenesis of synovitis in patients with rheumatoid arthritis (RA). Material and methods: Synovial tissues were obtained from patients with RA and osteoarthritis (OA) at the time of total knee arthroplasty. Immunohistochemistry was performed to determine the expression of Connexin 43 (Cx43) in the synovial tissues. The synovial tissues were cultured for 48 hours with various concentrations of a gap junction communication blocker (heptanol). The concentrations of TNF-α and metaloproteinases-3 (MMP-3) in the supernatants were measured using the enzyme immunoassay system (ELISA). In the preliminary stage, we had used 10 synovial tissues to determine the experimental conditions. Results: The concentrations of TNF-α and MMP-3 in supernatants decreased by adding gap junction blocker (heptanol). The expression of Cx43 was positive in the synovial

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Increased Intercellular Communication through Gap Junctions May Contribute to Progression of Osteoarthritis

Cited by 41 publications

References 26 publications

Fibroblast-like synoviocyte mechanosensitivity to fluid shear is modulated by interleukin-1α

Fibroblast-like synoviocyte mechanosensitivity to fluid shear is modulated by interleukin-1α

Identification of shoulder osteoarthritis biomarkers: comparison between shoulders with and without osteoarthritis

Experimental immunology Tumor necrosis factor-α and matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue is inhibited by blocking gap junction communication

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