IL-6/STAT3 signalling blockade protects against experimental osteoarthritis in mice

Latourte, Augustin; Maillet, Jérémy; Cherifi, Chahrazad; Ea, Hang‐Korng; Bouaziz, Wafa; Funck‐Brentano, Thomas; Cohen‐Solal, Martine; Haÿ, Eric; Richette, Pascal

doi:10.1016/j.joca.2016.01.674

Cited by 8 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been suggested that proinflammatory cytokines accelerate pain and joint destruction and are involved in the pathogenesis of OA (22). Neutralizing proinflammatory cytokines can attenuate OA development by inhibiting of joint inflammation (23, 24). In the present study, administration of iSTAT3-OA MSCs was associated with downregulated expression of proinflammatory cytokines in the joints of MIA-induced rats.…”

Section: Discussionmentioning

confidence: 99%

The Therapeutic Effect of STAT3 Signaling-Suppressed MSC on Pain and Articular Cartilage Damage in a Rat Model of Monosodium Iodoacetate-Induced Osteoarthritis

Lee

et al. 2018

Front. Immunol.

View full text Add to dashboard Cite

Osteoarthritis (OA) is a degenerative disease that induces pain, cartilage deformation, and joint inflammation. Mesenchymal stem cells (MSCs) are potential therapeutic agents for treatment of OA. However, MSC therapy can cause excessive inflammation. Signal transducer and activator of transcription 3 (STAT3) modulates secretion of many proinflammatory cytokines. Experimental OA was induced by intra-articular (IA) injection of monosodium iodoacetate (MIA) to the right knee of rats. MSCs from OA patients (OA-MSCs) were treated with STA21, a small molecule that blocks STAT3 signaling, by IA or intravenous (IV) injection after MIA injection. Pain severity was quantified by assessment of secondary tactile allodynia using the von Frey assessment test. Cartilage degradation was measured by microcomputed tomography image analysis, histological analysis, and the Mankin score. Protein and gene expression was evaluated by enzyme-linked immunosorbent assay, immunohistochemistry, and real-time polymerase chain reaction. MSCs increased production of proinflammatory cytokines under inflammatory conditions. STA21 significantly decreased expression of these proinflammatory molecules via inhibition of STAT3 activity but increased gene expression of molecules related to migration potential and immunomodulation in OA-MSCs. STAT3-inhibited OA-MSCs administrated by IV or IA injection decreased pain severity and cartilage damage in rats with MIA-induced OA rats by decreasing proinflammatory cytokines in the joints. Combined IA and IV-injected STAT3-inhibited OA-MSCs had an additive effect of pain relief in MIA-induced OA rats. STAT3 inhibition may optimize the therapeutic activities of MSCs for treating OA by attenuating pain and progression of MIA by inhibiting inflammation and cartilage damage.

show abstract

Section: Discussionmentioning

confidence: 99%

The Therapeutic Effect of STAT3 Signaling-Suppressed MSC on Pain and Articular Cartilage Damage in a Rat Model of Monosodium Iodoacetate-Induced Osteoarthritis

Lee

et al. 2018

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Furthermore, activation of the signal transducer and activator of transcription (Stat3) stimulates, while inactivation of Stat3 inhibits, OA initiation and progression (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis

Lai

Chen

et al. 2022

Nat Aging

View full text Add to dashboard Cite

Osteoarthritis (OA) is an aging-related degenerative joint disease, which has no cure partly due to limited understanding of its pathological mechanism(s). Here we report that the focal adhesion protein Kindlin-2, but not Kindlin-1 or -3, is highly expressed in articular chondrocytes of the hyaline cartilage, which is dramatically decreased in the degenerated articular cartilage of aged mice and patients with OA. Inducible deletion of Kindlin-2 in chondrocytes at adult stage leads to spontaneous OA and much severe OA lesions in the mice receiving the surgery of destabilization of the medial meniscus. Mechanistically, Kindlin-2 deficiency promotes mitochondrial oxidative stress and activates Stat3 in articular chondrocytes, leading to Runx2-mediated chondrocyte hypertrophic differentiation and catabolism. In vivo, systemic pharmacological blockade of Stat3 activation or genetic ablation of Stat3 in chondrocytes reverses aberrant accumulation of Runx2 and ECM-degrading enzymes and limits OA deteriorations caused by Kindlin-2 deficiency. Furthermore, genetic inactivation of Runx2 in chondrocytes reverses structural changes and OA lesions caused by Kindlin-2 deletion without down-regulating p-Stat3 in articular chondrocytes. Of translational significance, intraarticular injection of Kindlin-2-expressing adeno-associated virus decelerates progression of aging-and instability-induced knee joint OA in mice. Collectively, we identify a novel pathway comprising of Kindlin-2, Stat3 and Runx2 in articular chondrocytes responsible for maintaining integrity of the articular cartilage and define a potential therapeutic target for OA.

show abstract

“…A previous study recommended the use of anti-inflammatory agents in the treatment of OA based on the low-grade chronic inflammatory response associated with the pathogenesis of the disease and the resulting bone deformation [14]. Indeed, blocking IL-6 production prevents OA progression in animal models while NSAIDs suppress inflammatory cytokine levels in OA synovial fluid [15,16]. Metformin seems to have not only anti-glycemic but also anti-inflammatory effects [17].…”

Section: Discussionmentioning

confidence: 99%

Metformin improves monosodium-iodoacetate-induced osteoarthritis via regulation of pain mediators and autophagy-lysosomal pathway.

Kwon

Lee

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Osteoarthritis (OA) is the most common degenerative arthritis associated with pain and cartilage destruction in the elderly. Its pathogenesis involves inflammatory pathways. Metformin is used to treat type 2 diabetes but also exhibits regulation of autophagy pathway. This study investigated the ability of metformin to ameliorate the severity of monosodium iodoacetate (MIA)induced OA in rats.Methods Metformin was administered orally every day to rats with OA experimentally induced by intra-articular injection of MIA. Paw-withdrawal latency and threshold were used to assess pain severity. Cartilage damage and pain mediators in dorsal root ganglia were evaluated by histological analysis and a scoring system. Relative mRNA expression was measured by real-time PCR.Results Metformin ameliorated the progression of experimental OA and exhibited both antinociceptive properties and cartilage protection. The metformin-induced down-regulation of pain mediators, including CGRP, in dorsal root ganglia and protection against bone damage were also determined. In chondrocytes from OA patients, metformin decreased expression of genes encoding catabolic factors stimulated by interleukin-1β and inflammatory cell death factors and induced autophagosome-lysosome fusion phenotype. The combination therapy of metformin and celecoxib had significantly less cartilage damage than either the metformin alone group or the control group.Conclusions These results imply the possibility of therapeutic use of metformin in OA patients, based on its ability to suppress pain and protect cartilage. BackgroundOsteoarthritis (OA) is a chronic and degenerative arthritis and the most common continuous joint disorder in the elderly. The severe pain and irreversible cartilage damage associated with OA reduces the quality of life of affected patients [1]. Thus, treatment of OA is aimed at relieving arthralgia and preventing disease progression, including cartilage degradation, which is irreversible and may aggravate arthritic pain. However, effective disease-modifying osteoarthritis drugs that prevent cartilage damage in OA are not yet available [2]. While OA has traditionally been considered a noninflammatory arthritis, recent studies have shown that its pathogenesis includes low-grade 4 inflammation[3] and the involvement of numerous pro-inflammatory cytokines and matrix metalloproteinases (MMPs) in its aggravation [4]. Targeting of these pro-inflammatory cytokines has thus emerged as a therapeutic option in OA [4]. The destruction of bone and cartilage gives rises to a state of chronic inflammation [5] and is consistent with the finding of a smaller population of differentiated regulatory T (Treg) cells in the synovial membranes of OA vs. RA patients [6]. Interleukin (IL)-10 expression by Treg cells is also reduced in OA patients [7] whereas levels of helper T (Th) 17 cells in their joints are increased [8]. This imbalance of Th17/Treg, and therefore of pro-and antiinflammatory cytokines, may contribute to the pathogenesis of OA.The biguanide ...

show abstract

IL-6/STAT3 signalling blockade protects against experimental osteoarthritis in mice

Cited by 8 publications

References 0 publications

The Therapeutic Effect of STAT3 Signaling-Suppressed MSC on Pain and Articular Cartilage Damage in a Rat Model of Monosodium Iodoacetate-Induced Osteoarthritis

The Therapeutic Effect of STAT3 Signaling-Suppressed MSC on Pain and Articular Cartilage Damage in a Rat Model of Monosodium Iodoacetate-Induced Osteoarthritis

Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis

Metformin improves monosodium-iodoacetate-induced osteoarthritis via regulation of pain mediators and autophagy-lysosomal pathway.

Contact Info

Product

Resources

About