- Email: [email protected]
Survival in the rheumatoid synovium
Joint Bone Spine 78 (2011) 435–437
Editorial
Survival in the rheumatoid synovium
a r t i c l e
i n f o
Keywords: Rheumatoid arthritis Apoptosis Synoviocytes MiRNA Survival
It is now well established that synovial fibroblasts play a pivotal role in both initiation and perpetuation of rheumatoid arthritis (RA). These cells present the classic features of fibroblasts. They display however some unique properties including expression of cadherin 11, uridine diphosphoglucose dehydrogenase which reflects their ability to synthesize hyaluronan, VCAM-1, ICAM-1, integrin ␣41 and the decay accelerating factor (CD55) [1,2]. Under normal conditions, these cells are in a quiescent state. During RA, the intimal lining of the synovium that is relatively acellular shows a marked increase in cellularity. The synovial lining, which consists of one to two layers of cells, expands to a depth of 10 to 20 cell layers. These layers consist of two cell types; macrophages and mostly synovial fibroblasts or synoviocytes derivating from mesenchymal stem cells or from expansion of a stem cell pool in the synovium. This hyperplasia contributes to the formation of a pannus that will participate in the inflammatory process of destruction. In RA, this hyperplastic synovium behaves not only as a locally invasive tumor but synoviocytes have also the potential to invade unaffected joints and to contribute to the continuous spreading of the disease [3]. The mechanism of accumulation of synoviocytes remains to date unclear. Several studies demonstrated convincingly that abnormal proliferation of these cells could cause synovial hyperplasia. On the other hand, dysregulation of apoptosis might also be responsible of the accumulation of synoviocytes in the synovium and at the invasion site. It now appears that both statements do not exclude each other (Fig. 1). In RA, synoviocytes have a transformed phenotype characterized by proliferation and invasive ability. They expressed genes implicated in cell progression such as c-fos, c-jun, c-myc, jun-b, and erg-1 and underexpressed cyclin inhibitors such as Cip/Kip and INKA. Recent studies have identified a strong gain-of-function mutation, V600R, of the oncogene BRAF, which is an isoform of RAF, in synovial fibroblasts from two RA patients. This mutation is frequently found in melanoma and various cancers. Proliferation of synovial fibroblasts with V600R mutations is inhibited by
BRAF-specific siRNA, indicating that in some patients this mutation can be implicated in synoviocytes growth [4]. IL-17 can also induce proliferation by promoting overexpression of Cyr61 that is involved in cell adhesion, differentiation and proliferation [5]. Moreover, IL-17 protects also from apoptosis by promoting expression of Bcl-2 [6]. The most interesting fact is that synoviocytes exhibit a defect in apoptosis. Multiple mechanisms have been evoked to explain this resistance to apoptosis, affecting both the intrinsic pathway and the extrinsic pathway [7]. This resistance is mainly observed in synoviocytes of the surface layer involved in destruction, unlike synoviocytes in the deep layer of the synovial membrane where apoptosis can be readily identified. It is an important feature of synoviocytes as these cells are in a genetoxic environment that promotes apoptosis by the presence of abundant reactive oxygen species and nitrogen. Various studies revealed that the expression of anti-apoptotic molecules such as Bcl-2 [8] and Mcl-1 is increased in RA synoviocytes. Bcl-2 suppresses the initiation of cell death process and its up-regulation has been directly correlated to the accumulation of synoviocytes. Kurowska et al. [9] showed that an autocrine activation of IL-15Rs by synoviocyte-secreted IL-15, induces resistance to apoptosis of synoviocytes by enhancing expression of Bcl-2 and Bcl-X. More recent findings indicated that the metastasis-inducing protein, S100A4 or Mts-1, is up-regulated by synoviocytes in RA as compared to synoviocytes from osteoarthritis patients (OA). This up-regulation contributes to the stabilization of the p53 tumorsuppressor and regulates the p53 target genes including Bcl-2 [10]. In this issue of Joint Bone Spine, Sehong-Kyu et al. demonstrate that treatment of RA synoviocytes with the IL-6/sIL-6R complex increased Bcl-2 expression and that mellittin isolated from the venom of Apis mellifera enhanced apoptosis through suppression of Bcl-2 expression in RA synoviocytes [11]. Regarding the extrinsic pathway, Fas is expressed by RA synoviocytes but these cells are resistant to FasL-induced apoptosis which could be due to the presence of high concentrations of the soluble form of FasL. This could also explain the fact that TNF-␣ did not induce apoptosis in RA synoviocytes. Furthermore, TNF␣ cannot induce apoptosis through its receptor TNFR1 due to the strong activation of the NF-B pathway. Jab1, that has the ability to regulate the ubiquitination of TRAF2, may be involved in this effect [12]. PTEN, a phosphatase that dephosphorylates Akt, substrate of PI3-kinase that promotes survival by activating NF-B, has a decreased expression [13]. In the same way, clusterin which plays a pro-apoptotic role by inhibiting the NF-b pathway is also underexpressed in RA synoviocytes [14].
1297-319X/$ – see front matter © 2011 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2011.05.026
436
Editorial / Joint Bone Spine 78 (2011) 435–437
Fig. 1. Mechanisms of rheumatoid arthritis (RA) synoviocytes survival in the synovium.
The extrinsic pathway of apoptosis can also be activated by TRAIL. The role of this ligand in RA is controversial: the activation of RA synoviocytes by TRAIL leads to apoptosis to varying degrees, and even curiously to cell proliferation of surviving cells. Studies on murine models of collagen-induced arthritis have also demonstrated a protective role of TRAIL in RA pathology. The sensitivity of RA synoviocytes to TRAIL-induced apoptosis may depend on several factors, including the cell cycle and disease activity [15]. Other factors are also implicated. There is an increased expression of SUMO-1 that leads to the sumoylation of nuclear proteins and induces resistance to apoptosis. In addition, a negative correlation was identified between SUMO-1 and SENP1 with a decrease in this protease expression, which normally reverses the effect of SUMO-1 [16]. Survivin could also contribute to the inhibition of apoptosis. This protein is a member of the inhibitors of apoptosis family (IAP). High levels were found in the serum of patients with RA. It is produced by RA synoviocytes and contributes to the production of MMPs. Considering that extracellular survivin contributes to the survival of cancer cell lines, it is likely that this molecule is also involved in resistance to apoptosis of RA synoviocytes [17]. More recently, new factors have been identified that may affect apoptosis: microRNAs (miRNAs). MiRNAs are an evolutionarily conserved class of endogenous small non-coding RNAs, which are transcribed from intragenic or intergenic regions in pri-miRNAs and then processed by the ribonuclease Drosha in association with DGCR8. After being transported into the cytoplasm, the pre-miRNA is further processed by Dicer and its cofactor TRBP. One strand is then assembled in the RISC complex which always contains a member of the Argonaute family. The miRNA then guides the RISC complex to its target 3 -UTR leading to a decrease of mRNA stability or inhibition of translation. Some miRNAs have been shown to bind to the open reading frame or to the 5 -UTR of the target mRNA. In some cases, they can activate rather than inhibit gene expression. Regulation of miRNAs expression is controlled at the level of transcription, processing and subcellular localization. They were formerly thought to mainly repress translation of target mRNAs, but recently it was demonstrated that their main function is much more subtle and they should play a role rather by down regulating target mRNAs levels. They are probably as important as transcriptions factors. Apparailly [18] has recently published a review concerning miRNAs dysregulated in RA. Among them, some are more particularly implicated in the regulation of synoviocytes survival. There is now mounting evidence that miRNAs can regulate apoptosis in RA synoviocytes. A recent study showed that MiR-15a is a strong candidate for the regulation of Bcl-2 expression in synoviocytes.
MiR-15a down regulates Bcl-2 protein expression without affecting the stability of its mRNA. Nagata et al. [19] showed that MiR-15a expression is lower in the synovium of autoantibody-mediated arthritic mice than in healthy controls and this is in correlation with Bcl-2 strong up-regulation. Overexpression of MiR-15a complexed to atelocollagen into the synovium of arthritic mice decreased Bcl-2 protein expression and increased expression of caspase 3, as compared with the control group. But they were unable to show that the modulation of MiR-15a expression had any effect on the evolution of the disease. One possible reason is that miRNAs may cooperate to control the expression of their targets. MiR-15a belongs to the cluster miR15/miR16 which deletion or downregulation leads to Bcl-2 overexpression. Recent studies showed that reintroduction of this couple of miRNAs suppressed Bcl-2 expression in cancer cells and sensitized resistant cells to tamoxifen. Mcl-1, an anti-apoptotic protein of the Bcl-2 family, was recently shown to be targeted by miR-29b. MiR-29b expression is downregulated in various cancers such as breast, lung, prostate cancers and leukemia. Transfection of cells with miR-29b induced a decrease of Mcl-1 expression and sensitized the tumor cells to TRAIL cytotoxicity. Conversely, transfection of non-malignant cells (that express high levels of miR-29b) with a locked-nucleic acid antagonist of miR-29b increased Mcl-1 levels and reduced TRAIL-mediated apoptosis. MiR-29b could also play a role in promoting apoptosis by inducing increased expression of p53. This increase of apoptosis is correlated with a decrease in p85␣ and Cdc42 molecules that inhibit apoptosis mediated by p53 [20]. Preliminary results from our laboratory indicated that miR-29b is down regulated in RA synoviocytes activated with various TLR ligands. Its overexpression in synoviocytes induced apoptosis (unpublished data). Finally, data from Kawano and Nakamachi [21] indicated that miR-124a is downregulated in RA synoviocytes as compared with OA synoviocytes. Transfection of miR-124a precursor suppressed proliferation of RA synoviocytes by targeting CDK-2 and CDK-6 but did not induce cell death. The low expression of miR-124a might promote cell proliferation. Overall, these data indicate that miRNAs may play an important role in the regulation of inflammation [22] and also in the survival and proliferation of synoviocytes in RA. However, true functional data showing in vivo the exact effects on the disease are still required. In summary, RA synoviocytes are “protected” from death at number different levels that affected apoptosis and cell proliferation, thus these pathways provide interesting targets for therapeutic manipulation. A better understanding of miRNA biogenesis and function as well as advances in delivery of miRNA inhibitors and mimics constitute a new challenge for miRNA-based treatment of RA. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Naumann E, Lefevre S, Zimmermann B, et al. Rheumatoid arthritis progression mediated by activated synovial fibroblasts. Trends Mol Med 2010;16:458–68. [2] Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 2009;233:233–55. [3] Lefevre S, Knedla A, Tennie C, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med 2009;15:1414–20. [4] Weisbart RH, Chan G, Heinze E, et al. Braf drives synovial fibroblast transformation in rheumatoid arthritis. J Biol Chem 2010;285:34299–303. [5] Zhang Q, Wu J, Cao Q, et al. A critical role of Cyr61 in interleukin-17-dependent proliferation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Rheum 2009;60:3602–12. [6] Hot A, Miossec P. Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes. Ann Rheum Dis 2011;70:727–32.
Editorial / Joint Bone Spine 78 (2011) 435–437 [7] Korb A, Pavenstädt, Pap T. Cell death in rheumatoid arthritis. Apoptosis 2009;14:447–54. [8] Perlman H, Georganas C, Pagliari LJ, et al. Bcl-2 expression in synovial fibroblasts is essential for maintaining mitochondrial homeostasis and cell viability. J Immunol 2000;164:5227–35. [9] Kurowska M, Rudnicka W, Kontny E, et al. Fibroblast-like synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: endogenous IL-15 in autocrine fashion enhances cell proliferation and expression, of Bcl-x and Bcl-2. J Immunol 2002;169:1760–7. [10] Kligelhoffer J, Senolt L, Baslund B, et al. Up-regulation of metastasis promoting S100A4 (Mts-1) in rheumatoid arthritis: putative involvement in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 2007;56:779–89. [11] Seong-Kyu K, Ki-yeun P, Wern-Chan Y, et al. Melittin enhances apoptosis through suppression of IL-6/sIL-6R complex-induced NF-kB and STAT3 activation and Bcl-2 expression for human fibroblast-like synoviocytes in rheumatoid arthritis. Joint Bone Spine 2011, doi:10.1016/j.jbspin.2011.01.004. [12] Wang J, Li C, Liu Y, et al. JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to TNF-alpha. Am J Pathol 2006;169:8890–902. [13] Pap T, Franz JK, Hummel KM, et al. Activation of synovial fibroblasts in rheumatoid arthritis: lack of expression of the tumor suppressor PTEN at sites of invasive growth and destruction. Arthritis Res 2000;43:599–607. [14] Devauchelle V, Essabbani A, De Pinieux G, et al. Characterization and functional consequences of underexpression of clusterin in rheumatoid arthritis. J Immunol 2006;177:6471–9. [15] Audo R, Calmon-Hamaty F, Baeten D, et al. Mechanisms and clinical relevance of TRAIL-triggered responses in the synovial fibroblasts of patients with rheumatoid arthritis. Arthritis Rheum 2011;63:904–13. [16] Meinecke I, Pap G, Mendoza H, et al. Small ubiquitin-like modifier 1 [corrected] mediates the resistance of prosthesis-loosening fibroblast-like synoviocytes against Fas-induced apoptosis. Arthritis Rheum 2009;60:2065–70. [17] Ahn JK, Oh JM, Lee J, et al. Increased extracellular survivin in the synovial fluid of rheumatoid arthritis patients: fibroblast-like synoviocytes as a potential source of extracellular survivin. Inflammation 2010;33:381–8.
437
[18] Apparailly F. Looking for microRNA polymorphisms as new rheumatoid arthritis risk loci? Joint Bone Spine 2010;77:377–9. [19] Nagata Y, Nakasa T, Mochizuki Y, et al. Induction of apoptosis in the synovium of mice with auto-antibody-mediated arthritis by the intra-articular injection of double-stranded MicroRNA-15a. Arthritis Rheum 2009;60:2677–83. [20] Mott JL, Kobayashi S, Bronk SF, et al. Mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 2007;26:6133–40. [21] Kawano S, Nakamachi Y. MiR-124a as a key regulator of proliferaztion and MCP-1 secretion in synoviocytes from patients with rheumatoid arthritis. Ann Rheum Dis 2011;70:i88–91. [22] Alsaleh G, Suffert G, Semaan N, et al. Bruton’s tyrosine kinase is involved in miR-346-related regulation of IL-18 release by lipopolysaccharide-activated rheumatoid fibroblast-like synoviocytes. J Immunol 2009;182:5088–97.
Dominique Wachsmann ∗ Jean Sibilia EA 4438, laboratoire physiopathologie des arthrites, université de Strasbourg, 74, route du Rhin, 67401 Illkirch, France ∗ Corresponding
author. E-mail address: [email protected] (D. Wachsmann) 26 May 2011 Available online31 July 2011
Editorial
Survival in the rheumatoid synovium
a r t i c l e
i n f o
Keywords: Rheumatoid arthritis Apoptosis Synoviocytes MiRNA Survival
It is now well established that synovial fibroblasts play a pivotal role in both initiation and perpetuation of rheumatoid arthritis (RA). These cells present the classic features of fibroblasts. They display however some unique properties including expression of cadherin 11, uridine diphosphoglucose dehydrogenase which reflects their ability to synthesize hyaluronan, VCAM-1, ICAM-1, integrin ␣41 and the decay accelerating factor (CD55) [1,2]. Under normal conditions, these cells are in a quiescent state. During RA, the intimal lining of the synovium that is relatively acellular shows a marked increase in cellularity. The synovial lining, which consists of one to two layers of cells, expands to a depth of 10 to 20 cell layers. These layers consist of two cell types; macrophages and mostly synovial fibroblasts or synoviocytes derivating from mesenchymal stem cells or from expansion of a stem cell pool in the synovium. This hyperplasia contributes to the formation of a pannus that will participate in the inflammatory process of destruction. In RA, this hyperplastic synovium behaves not only as a locally invasive tumor but synoviocytes have also the potential to invade unaffected joints and to contribute to the continuous spreading of the disease [3]. The mechanism of accumulation of synoviocytes remains to date unclear. Several studies demonstrated convincingly that abnormal proliferation of these cells could cause synovial hyperplasia. On the other hand, dysregulation of apoptosis might also be responsible of the accumulation of synoviocytes in the synovium and at the invasion site. It now appears that both statements do not exclude each other (Fig. 1). In RA, synoviocytes have a transformed phenotype characterized by proliferation and invasive ability. They expressed genes implicated in cell progression such as c-fos, c-jun, c-myc, jun-b, and erg-1 and underexpressed cyclin inhibitors such as Cip/Kip and INKA. Recent studies have identified a strong gain-of-function mutation, V600R, of the oncogene BRAF, which is an isoform of RAF, in synovial fibroblasts from two RA patients. This mutation is frequently found in melanoma and various cancers. Proliferation of synovial fibroblasts with V600R mutations is inhibited by
BRAF-specific siRNA, indicating that in some patients this mutation can be implicated in synoviocytes growth [4]. IL-17 can also induce proliferation by promoting overexpression of Cyr61 that is involved in cell adhesion, differentiation and proliferation [5]. Moreover, IL-17 protects also from apoptosis by promoting expression of Bcl-2 [6]. The most interesting fact is that synoviocytes exhibit a defect in apoptosis. Multiple mechanisms have been evoked to explain this resistance to apoptosis, affecting both the intrinsic pathway and the extrinsic pathway [7]. This resistance is mainly observed in synoviocytes of the surface layer involved in destruction, unlike synoviocytes in the deep layer of the synovial membrane where apoptosis can be readily identified. It is an important feature of synoviocytes as these cells are in a genetoxic environment that promotes apoptosis by the presence of abundant reactive oxygen species and nitrogen. Various studies revealed that the expression of anti-apoptotic molecules such as Bcl-2 [8] and Mcl-1 is increased in RA synoviocytes. Bcl-2 suppresses the initiation of cell death process and its up-regulation has been directly correlated to the accumulation of synoviocytes. Kurowska et al. [9] showed that an autocrine activation of IL-15Rs by synoviocyte-secreted IL-15, induces resistance to apoptosis of synoviocytes by enhancing expression of Bcl-2 and Bcl-X. More recent findings indicated that the metastasis-inducing protein, S100A4 or Mts-1, is up-regulated by synoviocytes in RA as compared to synoviocytes from osteoarthritis patients (OA). This up-regulation contributes to the stabilization of the p53 tumorsuppressor and regulates the p53 target genes including Bcl-2 [10]. In this issue of Joint Bone Spine, Sehong-Kyu et al. demonstrate that treatment of RA synoviocytes with the IL-6/sIL-6R complex increased Bcl-2 expression and that mellittin isolated from the venom of Apis mellifera enhanced apoptosis through suppression of Bcl-2 expression in RA synoviocytes [11]. Regarding the extrinsic pathway, Fas is expressed by RA synoviocytes but these cells are resistant to FasL-induced apoptosis which could be due to the presence of high concentrations of the soluble form of FasL. This could also explain the fact that TNF-␣ did not induce apoptosis in RA synoviocytes. Furthermore, TNF␣ cannot induce apoptosis through its receptor TNFR1 due to the strong activation of the NF-B pathway. Jab1, that has the ability to regulate the ubiquitination of TRAF2, may be involved in this effect [12]. PTEN, a phosphatase that dephosphorylates Akt, substrate of PI3-kinase that promotes survival by activating NF-B, has a decreased expression [13]. In the same way, clusterin which plays a pro-apoptotic role by inhibiting the NF-b pathway is also underexpressed in RA synoviocytes [14].
1297-319X/$ – see front matter © 2011 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2011.05.026
436
Editorial / Joint Bone Spine 78 (2011) 435–437
Fig. 1. Mechanisms of rheumatoid arthritis (RA) synoviocytes survival in the synovium.
The extrinsic pathway of apoptosis can also be activated by TRAIL. The role of this ligand in RA is controversial: the activation of RA synoviocytes by TRAIL leads to apoptosis to varying degrees, and even curiously to cell proliferation of surviving cells. Studies on murine models of collagen-induced arthritis have also demonstrated a protective role of TRAIL in RA pathology. The sensitivity of RA synoviocytes to TRAIL-induced apoptosis may depend on several factors, including the cell cycle and disease activity [15]. Other factors are also implicated. There is an increased expression of SUMO-1 that leads to the sumoylation of nuclear proteins and induces resistance to apoptosis. In addition, a negative correlation was identified between SUMO-1 and SENP1 with a decrease in this protease expression, which normally reverses the effect of SUMO-1 [16]. Survivin could also contribute to the inhibition of apoptosis. This protein is a member of the inhibitors of apoptosis family (IAP). High levels were found in the serum of patients with RA. It is produced by RA synoviocytes and contributes to the production of MMPs. Considering that extracellular survivin contributes to the survival of cancer cell lines, it is likely that this molecule is also involved in resistance to apoptosis of RA synoviocytes [17]. More recently, new factors have been identified that may affect apoptosis: microRNAs (miRNAs). MiRNAs are an evolutionarily conserved class of endogenous small non-coding RNAs, which are transcribed from intragenic or intergenic regions in pri-miRNAs and then processed by the ribonuclease Drosha in association with DGCR8. After being transported into the cytoplasm, the pre-miRNA is further processed by Dicer and its cofactor TRBP. One strand is then assembled in the RISC complex which always contains a member of the Argonaute family. The miRNA then guides the RISC complex to its target 3 -UTR leading to a decrease of mRNA stability or inhibition of translation. Some miRNAs have been shown to bind to the open reading frame or to the 5 -UTR of the target mRNA. In some cases, they can activate rather than inhibit gene expression. Regulation of miRNAs expression is controlled at the level of transcription, processing and subcellular localization. They were formerly thought to mainly repress translation of target mRNAs, but recently it was demonstrated that their main function is much more subtle and they should play a role rather by down regulating target mRNAs levels. They are probably as important as transcriptions factors. Apparailly [18] has recently published a review concerning miRNAs dysregulated in RA. Among them, some are more particularly implicated in the regulation of synoviocytes survival. There is now mounting evidence that miRNAs can regulate apoptosis in RA synoviocytes. A recent study showed that MiR-15a is a strong candidate for the regulation of Bcl-2 expression in synoviocytes.
MiR-15a down regulates Bcl-2 protein expression without affecting the stability of its mRNA. Nagata et al. [19] showed that MiR-15a expression is lower in the synovium of autoantibody-mediated arthritic mice than in healthy controls and this is in correlation with Bcl-2 strong up-regulation. Overexpression of MiR-15a complexed to atelocollagen into the synovium of arthritic mice decreased Bcl-2 protein expression and increased expression of caspase 3, as compared with the control group. But they were unable to show that the modulation of MiR-15a expression had any effect on the evolution of the disease. One possible reason is that miRNAs may cooperate to control the expression of their targets. MiR-15a belongs to the cluster miR15/miR16 which deletion or downregulation leads to Bcl-2 overexpression. Recent studies showed that reintroduction of this couple of miRNAs suppressed Bcl-2 expression in cancer cells and sensitized resistant cells to tamoxifen. Mcl-1, an anti-apoptotic protein of the Bcl-2 family, was recently shown to be targeted by miR-29b. MiR-29b expression is downregulated in various cancers such as breast, lung, prostate cancers and leukemia. Transfection of cells with miR-29b induced a decrease of Mcl-1 expression and sensitized the tumor cells to TRAIL cytotoxicity. Conversely, transfection of non-malignant cells (that express high levels of miR-29b) with a locked-nucleic acid antagonist of miR-29b increased Mcl-1 levels and reduced TRAIL-mediated apoptosis. MiR-29b could also play a role in promoting apoptosis by inducing increased expression of p53. This increase of apoptosis is correlated with a decrease in p85␣ and Cdc42 molecules that inhibit apoptosis mediated by p53 [20]. Preliminary results from our laboratory indicated that miR-29b is down regulated in RA synoviocytes activated with various TLR ligands. Its overexpression in synoviocytes induced apoptosis (unpublished data). Finally, data from Kawano and Nakamachi [21] indicated that miR-124a is downregulated in RA synoviocytes as compared with OA synoviocytes. Transfection of miR-124a precursor suppressed proliferation of RA synoviocytes by targeting CDK-2 and CDK-6 but did not induce cell death. The low expression of miR-124a might promote cell proliferation. Overall, these data indicate that miRNAs may play an important role in the regulation of inflammation [22] and also in the survival and proliferation of synoviocytes in RA. However, true functional data showing in vivo the exact effects on the disease are still required. In summary, RA synoviocytes are “protected” from death at number different levels that affected apoptosis and cell proliferation, thus these pathways provide interesting targets for therapeutic manipulation. A better understanding of miRNA biogenesis and function as well as advances in delivery of miRNA inhibitors and mimics constitute a new challenge for miRNA-based treatment of RA. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Naumann E, Lefevre S, Zimmermann B, et al. Rheumatoid arthritis progression mediated by activated synovial fibroblasts. Trends Mol Med 2010;16:458–68. [2] Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 2009;233:233–55. [3] Lefevre S, Knedla A, Tennie C, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med 2009;15:1414–20. [4] Weisbart RH, Chan G, Heinze E, et al. Braf drives synovial fibroblast transformation in rheumatoid arthritis. J Biol Chem 2010;285:34299–303. [5] Zhang Q, Wu J, Cao Q, et al. A critical role of Cyr61 in interleukin-17-dependent proliferation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Rheum 2009;60:3602–12. [6] Hot A, Miossec P. Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes. Ann Rheum Dis 2011;70:727–32.
Editorial / Joint Bone Spine 78 (2011) 435–437 [7] Korb A, Pavenstädt, Pap T. Cell death in rheumatoid arthritis. Apoptosis 2009;14:447–54. [8] Perlman H, Georganas C, Pagliari LJ, et al. Bcl-2 expression in synovial fibroblasts is essential for maintaining mitochondrial homeostasis and cell viability. J Immunol 2000;164:5227–35. [9] Kurowska M, Rudnicka W, Kontny E, et al. Fibroblast-like synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: endogenous IL-15 in autocrine fashion enhances cell proliferation and expression, of Bcl-x and Bcl-2. J Immunol 2002;169:1760–7. [10] Kligelhoffer J, Senolt L, Baslund B, et al. Up-regulation of metastasis promoting S100A4 (Mts-1) in rheumatoid arthritis: putative involvement in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 2007;56:779–89. [11] Seong-Kyu K, Ki-yeun P, Wern-Chan Y, et al. Melittin enhances apoptosis through suppression of IL-6/sIL-6R complex-induced NF-kB and STAT3 activation and Bcl-2 expression for human fibroblast-like synoviocytes in rheumatoid arthritis. Joint Bone Spine 2011, doi:10.1016/j.jbspin.2011.01.004. [12] Wang J, Li C, Liu Y, et al. JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to TNF-alpha. Am J Pathol 2006;169:8890–902. [13] Pap T, Franz JK, Hummel KM, et al. Activation of synovial fibroblasts in rheumatoid arthritis: lack of expression of the tumor suppressor PTEN at sites of invasive growth and destruction. Arthritis Res 2000;43:599–607. [14] Devauchelle V, Essabbani A, De Pinieux G, et al. Characterization and functional consequences of underexpression of clusterin in rheumatoid arthritis. J Immunol 2006;177:6471–9. [15] Audo R, Calmon-Hamaty F, Baeten D, et al. Mechanisms and clinical relevance of TRAIL-triggered responses in the synovial fibroblasts of patients with rheumatoid arthritis. Arthritis Rheum 2011;63:904–13. [16] Meinecke I, Pap G, Mendoza H, et al. Small ubiquitin-like modifier 1 [corrected] mediates the resistance of prosthesis-loosening fibroblast-like synoviocytes against Fas-induced apoptosis. Arthritis Rheum 2009;60:2065–70. [17] Ahn JK, Oh JM, Lee J, et al. Increased extracellular survivin in the synovial fluid of rheumatoid arthritis patients: fibroblast-like synoviocytes as a potential source of extracellular survivin. Inflammation 2010;33:381–8.
437
[18] Apparailly F. Looking for microRNA polymorphisms as new rheumatoid arthritis risk loci? Joint Bone Spine 2010;77:377–9. [19] Nagata Y, Nakasa T, Mochizuki Y, et al. Induction of apoptosis in the synovium of mice with auto-antibody-mediated arthritis by the intra-articular injection of double-stranded MicroRNA-15a. Arthritis Rheum 2009;60:2677–83. [20] Mott JL, Kobayashi S, Bronk SF, et al. Mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 2007;26:6133–40. [21] Kawano S, Nakamachi Y. MiR-124a as a key regulator of proliferaztion and MCP-1 secretion in synoviocytes from patients with rheumatoid arthritis. Ann Rheum Dis 2011;70:i88–91. [22] Alsaleh G, Suffert G, Semaan N, et al. Bruton’s tyrosine kinase is involved in miR-346-related regulation of IL-18 release by lipopolysaccharide-activated rheumatoid fibroblast-like synoviocytes. J Immunol 2009;182:5088–97.
Dominique Wachsmann ∗ Jean Sibilia EA 4438, laboratoire physiopathologie des arthrites, université de Strasbourg, 74, route du Rhin, 67401 Illkirch, France ∗ Corresponding
author. E-mail address: [email protected] (D. Wachsmann) 26 May 2011 Available online31 July 2011