Pathophysiology of osteoarthritis: canonical NF-κB/IKKβ-dependent and kinase-independent effects of IKKα in cartilage degradation and chondrocyte differentiation

Olivotto, Eleonora; Otero, Miguel; Marcu, Kenneth B.; Goldring, Mary B.

doi:10.1136/rmdopen-2015-000061

Cited by 110 publications

(84 citation statements)

References 66 publications

(64 reference statements)

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“…Aging is associated with inflammation through acquisition of a senescence‐associated secretory phenotype (SASP) with IL‐6 and IL‐1 being the most prominent cytokines (Coppe, Desprez, Krtolica & Campisi, 2010). Furthermore, mechanical overloading induces translocation of NF‐κB into the nucleus, stimulation of NF‐κB signaling pathway, and IL‐6 transcription activation in chondrocytes (Marcu, Otero, Olivotto, Borzi & Goldring, 2010; Olivotto, Otero, Marcu & Goldring, 2015). Therefore, biochemical and biomechanical crosstalk among different tissue compartments likely plays an important role in the onset and progression of OA by initiation and maintenance of a persistent low‐grade pro‐inflammatory environment in the joint (Little & Hunter, 2013).…”

Section: Discussionmentioning

confidence: 99%

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

Guan

Yang

et al. 2018

Aging Cell

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SummaryPrimary osteoarthritis (OA) is associated with aging, while post‐traumatic OA (PTOA) is associated with mechanical injury and inflammation. It is not clear whether the two types of osteoarthritis share common mechanisms. We found that miR‐146a, a microRNA‐associated with inflammation, is activated by cyclic load in the physiological range but suppressed by mechanical overload in human articular chondrocytes. Furthermore, miR‐146a expression is decreased in the OA lesions of human articular cartilage. To understand the role of miR‐146a in osteoarthritis, we systemically characterized mice in which miR‐146a is either deficient in whole body or overexpressed in chondrogenic cells specifically. miR‐146a‐deficient mice develop early onset of OA characterized by cartilage degeneration, synovitis, and osteophytes. Conversely, miR‐146a chondrogenic overexpressing mice are resistant to aging‐associated OA. Loss of miR‐146a exacerbates articular cartilage degeneration during PTOA, while chondrogenic overexpression of miR‐146a inhibits PTOA. Thus, miR‐146a inhibits both OA and PTOA in mice, suggesting a common protective mechanism initiated by miR‐146a. miR‐146a suppresses IL‐1β of catabolic factors, and we provide evidence that miR‐146a directly inhibits Notch1 expression. Therefore, such inhibition of Notch1 may explain suppression of inflammatory mediators by miR‐146a. Chondrogenic overexpression of miR‐146a or intra‐articular administration of a Notch1 inhibitor alleviates IL‐1β‐induced catabolism and rescues joint degeneration in miR‐146a‐deficient mice, suggesting that miR‐146a is sufficient to protect OA pathogenesis by inhibiting Notch signaling in the joint. Thus, miR‐146a may be used to counter both aging‐associated OA and mechanical injury‐/inflammation‐induced PTOA.

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Section: Discussionmentioning

confidence: 99%

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

Guan

Yang

et al. 2018

Aging Cell

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“…Many experimental studies using human samples have shown that activation of NF-κB signalling in chondrocytes and synovial cells is closely involved in enhanced production of inflammatory cytokines or catabolic enzymes [51]. Similarly, previous studies have shown enhanced expression of Notch-related molecules in human OA cartilage [52].…”

Section: Prospectsmentioning

confidence: 99%

Molecular mechanisms underlying osteoarthritis development: Notch and NF-κB

2017

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Osteoarthritis (OA) is a multi-factorial and highly prevalent joint disorder worldwide. Since the establishment of murine surgical knee OA models in 2005, many of the key molecules and signalling pathways responsible for OA development have been identified. Here we review the roles of two multi-functional signalling pathways in OA development: Notch and nuclear factor kappa-light-chain-enhancer of activated B cells. Previous studies have identified various aspects of articular chondrocyte regulation by these pathways. However, comprehensive understanding of the molecular networks regulating articular cartilage homeostasis and OA pathogenesis is needed.

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“…In OA chondrocytes, canonical NF-κB signaling mediates the induction of inflammatory mediators and catabolic mechanisms as well as cellular differentiation changes which favor the onset and perpetuation of disease [44, 45]. A reduction in the activation of this transcription factor by CM and EV could contribute to the observed downregulation of IL-6, TNFα, COX-2, iNOS and MMPs [46].…”

Section: Discussionmentioning

confidence: 99%

Microvesicles from Human Adipose Tissue-Derived Mesenchymal Stem Cells as a New Protective Strategy in Osteoarthritic Chondrocytes

Tofiño-Vian

Guillén

Caz

et al. 2018

Cell Physiol Biochem

175

141

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Background/Aims: Chronic inflammation contributes to cartilage degeneration during the progression of osteoarthritis (OA). Adipose tissue-derived mesenchymal stem cells (AD-MSC) show great potential to treat inflammatory and degradative processes in OA and have demonstrated paracrine effects in chondrocytes. In the present work, we have isolated and characterized the extracellular vesicles from human AD-MSC to investigate their role in the chondroprotective actions of these cells. Methods: AD-MSC were isolated by collagenase treatment from adipose tissue from healthy individuals subjected to abdominal lipectomy surgery. Microvesicles and exosomes were obtained from conditioned medium by filtration and differential centrifugation. Chondrocytes from OA patients were used in primary culture and stimulated with 10 ng/ml interleukin(IL)-1β in the presence or absence of AD-MSC microvesicles, exosomes or conditioned medium. Protein expression was investigated by ELISA and immunofluorescence, transcription factor-DNA binding by ELISA, gene expression by real-time PCR, prostaglandin E₂ (PGE₂) by radioimmunoassay, and matrix metalloproteinase (MMP) activity and nitric oxide (NO) production by fluorometry. Results: In OA chondrocytes stimulated with IL-1β, microvesicles and exosomes reduced the production of inflammatory mediators tumor necrosis factor-α, IL-6, PGE₂ and NO. The downregulation of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 would lead to the decreased PGE₂ production while the effect on NO could depend on the reduction of inducible nitric oxide synthase expression. Treatment of OA chondrocytes with extracellular vesicles also decreased the release of MMP activity and MMP-13 expression whereas the production of the anti-inflammatory cytokine IL-10 and the expression of collagen II were significantly enhanced. The reduction of inflammatory and catabolic mediators could be the consequence of a lower activation of nuclear factor-κB and activator protein-1. The upregulation of annexin A1 specially in MV may contribute to the anti-inflammatory and chondroprotective effects of AD-MSC. Conclusions: Our data support the interest of AD-MSC extracellular vesicles to develop new therapeutic approaches in joint conditions.

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Pathophysiology of osteoarthritis: canonical NF-κB/IKKβ-dependent and kinase-independent effects of IKKα in cartilage degradation and chondrocyte differentiation

Cited by 110 publications

References 66 publications

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

Molecular mechanisms underlying osteoarthritis development: Notch and NF-κB

Microvesicles from Human Adipose Tissue-Derived Mesenchymal Stem Cells as a New Protective Strategy in Osteoarthritic Chondrocytes

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