ADAM15 in Apoptosis Resistance of Synovial Fibroblasts: Converting Fas/CD95 Death Signals Into the Activation of Prosurvival Pathways by Calmodulin Recruitment

Janczi, Tomasz; Böhm, Beate; Fehrl, Yuliya; DeGiacomo, Pangrazio; Kinne, Raimund W.; Burkhardt, Harald

doi:10.1002/art.40667

Cited by 7 publications

(8 citation statements)

References 36 publications

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“…In addition, proteasome inhibition has been discussed to prevent the breakdown of pro‐apoptotic factors . RASF are known to have an increased resistance to apoptosis and increased survival . Therefore, we evaluated the effect of bortezomib on RASF in the SCID mouse model.…”

Section: Discussionmentioning

confidence: 99%

“…37 RASF are known to have an increased resistance to apoptosis and increased survival. 38 Therefore, we evaluated the effect of bortezomib on RASF in the SCID mouse model. RASF-mediated cartilage invasion at the ipsilateral site (cartilage implanted with RASF) and at the contralateral site (cartilage implanted without RASF) was not altered by bortezomib suggesting that the inhibition of proteasome activity, potentially affecting apoptosis and RASF survival, does not play a crucial role in this system.…”

Section: Discussionmentioning

confidence: 99%

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Interactions between rheumatoid arthritis synovial fibroblast migration and endothelial cells

et al. 2018

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Leukocytes travel within the circulation and enter connective tissues by interactions with endothelium of postcapillary venules mediated by cell adhesion molecules, summarized as the leukocyte adhesion cascade. In the severe combined immunodeficient (SCID) mouse model, rheumatoid arthritis (RA) synovial fibroblasts (SF) migrated to distant cartilage through the vasculature. Therefore, RASF adhesion toward endothelial cells (EC) and E‐ and P‐selectins were analyzed. Cell‐to‐cell binding assays between SF and EC were performed. Interactions of SF with tumor necrosis factor α (TNFα)‐activated EC or selectins were analyzed in flow adhesion assays. Immunohistochemistry for E‐selectin ligand CD15s was performed. CD15s induction in RASF by human serum or media was evaluated. Wild‐type and E‐/‐/P‐/‐Selectin‐SCID mice were used for inverse‐wrap surgery. After laser‐mediated microdissection, real‐time PCR for E‐/P‐selectin/vascular cell adhesion molecule 1 was performed. Adhesion between SF/EC under static conditions was highest in Roswell Park Memorial Institute‐cultured RASF to TNFαα‐activated human umbilical vein endothelial cells (2.25‐fold) and RASF adhesion was higher toward venous than arterial EC (Dulbecco's modified eagle medium P = 0.0419, RPMI P = 0.0119). In flow chamber assays, RASF adhesion to E‐selectin was higher than to P‐selectin (e.g. 0.9 dyn cm−2 P = 0.0001). Osteoarthritis synovial fibroblasts showed lower rolling/adhesion properties (e.g. 0.5 dyn cm−2, P = 0.0010). RASF adhesion to TNFαα‐activated EC was increased (e.g. 0.9 dyn cm−2, P = 0.0061). CD15s induction in RASF was strongest in RA serum. Vimentin/CD15s double‐positive cells were detectable. In E‐/P‐selectin‐deficient mice, contralateral invasion was reduced (P = 0.023). E‐ and P‐selectin, and vascular cell adhesion molecule 1 expression in EC of implants was confirmed. Our data indicate that the milieu within vessels induces CD15s which enables RASF to interact with E‐selectin/EC under flow. Therefore, RASF may migrate to distant sites and leave the vasculature similarly to leukocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interactions between rheumatoid arthritis synovial fibroblast migration and endothelial cells

et al. 2018

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“…In this respect, our investigations provide additional new mechanistic insights into mechano-induced SIRT1 upregulation in SF regarding the crucial dependency of ADAM15. Moreover, as ADAM15 is known for various anti-apoptotic effects on synovial fibroblasts [16,18], its newly elucidated impact on mechanically regulated SIRT1 may complement the already revealed spectrum of mechanisms with a modulatory effect on deacetylase activity. The tumor suppressor p53 is a well-studied SIRT1 target [44], whose inactivation by deacetylation causes increased apoptosis resistance to oxidative and genotoxic stress [45,46], thereby likely promoting the aggressive growth of inflamed synovial tissue.…”

Section: Discussionmentioning

confidence: 96%

“…A central focus of our investigation was the elucidation of the upstream mechanotransduction pathway; in particular, the molecular interactions with ADAM15. In addition to known ADAM15-mediated Src signaling [16,18,19], the activation of c-jun/JNK, which had already been implicated in the mechanosensing of fibroblasts from other tissues [48][49][50], turned out to be the critical MAPK pathway in the regulation of HOTAIR/SIRT1. Moreover, the described mechanotransduction pathways leading to JNK activation also involve Ca 2+dependent mechanisms [50,51].…”

Section: Discussionmentioning

confidence: 99%

“…ADAM15 enhances the cell adhesion of chondrocytes to collagen type II, and its pro-domain-containing fibronectin-type II and III domains bind to native collagen type II [17]. It functions as a trigger of anti-apoptotic signaling pathways, elicited by various death stimuli through the binding and activation of the "survival kinases" Src and FAK [16,18,19].…”

Section: Introductionmentioning

confidence: 99%

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A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts

Janczi

Meier

Fehrl

et al. 2021

Cells

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Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial joints, while excessive loading is a factor promoting the inflammatory mechanisms of joint destruction. Here, we describe a mechanotransduction pathway in synovial fibroblasts (SF) derived from the synovial membrane of inflamed joints. The functionality of this pathway is completely lost in the absence of the disintegrin metalloproteinase ADAM15 strongly upregulated in SF. The mechanosignaling events involve the Ca2+-dependent activation of c-Jun-N-terminal kinases, the subsequent downregulation of long noncoding RNA HOTAIR, and upregulation of the metabolic energy sensor sirtuin-1. This afferent loop of the pathway is facilitated by ADAM15 via promoting the cell membrane density of the constitutively cycling mechanosensitive transient receptor potential vanilloid 4 calcium channels. In addition, ADAM15 reinforces the Src-mediated activation of pannexin-1 channels required for the enhanced release of ATP, a mediator of purinergic inflammation, which is increasingly produced upon sirtuin-1 induction.

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Osteoarthritis: pathogenic signaling pathways and therapeutic targets

Yao

Tao

et al. 2023

Sig Transduct Target Ther

294

147

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Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed to be caused by the wearing and tearing of articular cartilage, but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues, which leads to the histological and structural changes of the joint and ends up with the whole tissue dysfunction. Currently, there is no cure for OA, partly due to a lack of comprehensive understanding of the pathological mechanism of the initiation and progression of the disease. Therefore, a better understanding of pathological signaling pathways and key molecules involved in OA pathogenesis is crucial for therapeutic target design and drug development. In this review, we first summarize the epidemiology of OA, including its prevalence, incidence and burdens, and OA risk factors. We then focus on the roles and regulation of the pathological signaling pathways, such as Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP and FGF signaling pathways, and key regulators AMPK, mTOR, and RUNX2 in the onset and development of OA. In addition, the roles of factors associated with OA, including MMPs, ADAMTS/ADAMs, and PRG4, are discussed in detail. Finally, we provide updates on the current clinical therapies and clinical trials of biological treatments and drugs for OA. Research advances in basic knowledge of articular cartilage biology and OA pathogenesis will have a significant impact and translational value in developing OA therapeutic strategies.

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ADAM15 in Apoptosis Resistance of Synovial Fibroblasts: Converting Fas/CD95 Death Signals Into the Activation of Prosurvival Pathways by Calmodulin Recruitment

Abstract: ADAM15 provides a scaffold for formation of CaM-dependent prosurvival signaling complexes upon CRAC/Orai coactivation by FasL-induced death signals and a potential therapeutic target to break apoptosis resistance in RASFs.

Cited by 7 publications

References 36 publications

Interactions between rheumatoid arthritis synovial fibroblast migration and endothelial cells

Interactions between rheumatoid arthritis synovial fibroblast migration and endothelial cells

A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts

Osteoarthritis: pathogenic signaling pathways and therapeutic targets

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