The catabolic pathway mediated by Toll‐like receptors in human osteoarthritic chondrocytes

Kim, Hyun Ah; Cho, Mi‐La; Choi, Hye Young; Yoon, Chanho; Jhun, Joo Yeon; Oh, Hey Jwa; Kim, Ho-Youn

doi:10.1002/art.21951

Cited by 245 publications

(229 citation statements)

References 32 publications

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“…There is considerable evidence implicating NO in joint inflammation and cartilage degradation in RA (40). TLR-2 and TLR-4 strongly induce the production of NO and MMPs in first-passage osteoarthritic chondrocytes, and promote the degradation of proteoglycans and type II collagen in osteoarthritic cartilage explants (41). Since TLR-2 and TLR-4 mRNA are expressed at low levels on naive patellar chondrocytes and is up-regulated during the SCW arthritis (data not shown), the reduction in iNOS expression in cartilage from the TLR-4 -/-mice might be a direct effect of TLR-4 activation on chondrocytes, or it may reflect the reduced inflammation in these mice.…”

Section: Discussionmentioning

confidence: 99%

Shift from toll‐like receptor 2 (TLR‐2) toward TLR‐4 dependency in the erosive stage of chronic streptococcal cell wall arthritis coincident with TLR‐4–mediated interleukin‐17 production

Abdollahi‐Roodsaz¹,

Joosten²,

Helsen³

et al. 2008

Arthritis & Rheumatism

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Section: Discussionmentioning

confidence: 99%

Shift from toll‐like receptor 2 (TLR‐2) toward TLR‐4 dependency in the erosive stage of chronic streptococcal cell wall arthritis coincident with TLR‐4–mediated interleukin‐17 production

Abdollahi‐Roodsaz¹,

Joosten²,

Helsen³

et al. 2008

Arthritis & Rheumatism

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“…In humans, 11 TLR homologs have been identified thus far, expressed by numerous cell types like monocytes and dendritic cells, 1 and for example by chondrocytes. 2 TLRs detect microbial components, but TLR2 and TLR4 also recognize endogenous ligands like heat-shock proteins, necrotic cells, hyaluronan, and fibronectin. 1 Ligand recognition elicits an immune response with upregulation and activation of proinflammatory cytokines and matrix-metalloproteinases (MMPs).…”

mentioning

confidence: 99%

“…1 Ligand recognition elicits an immune response with upregulation and activation of proinflammatory cytokines and matrix-metalloproteinases (MMPs). 2 Hence, via endogenous ligand recognition the TLR-mediated catabolic signalling pathways can directly contribute to degradative tissue reactions even in the absence of microbial components. TLRs are implicated in inflammatory and autoimmune diseases, but also in disorders like atherosclerosis and cancer.…”

mentioning

confidence: 99%

“…3,4 Furthermore they play a role in noninfected rheumatoid arthritis (RA) and in the primarily degenerative joint disease osteoarthritis (OA). [1][2][3]5,6 In degenerative tendinopathies the balance between matrix synthesis and degradation is disturbed, and increased MMP activity as well as an increased percentage of degraded collagen are found. [7][8][9] An increase in NO synthase expression was found in a supraspinatus tendon overuse model 10 and an increase in COX2, a key regulator of prostaglandin synthesis was found in patellar tendinopathy.…”

mentioning

confidence: 99%

“…11 These catabolic activities can be influenced by TLR signalling, as shown in experiments with chondrocytes. 2,6 Furthermore, increased expression of subunit B of the endogenous TLR ligand fibronectin has been found in Achilles tendinopathy. 12 The presence of other endogenous TLR ligands known so far (heat-shock proteins, necrotic cells, hyaluronan) in tendinopathy is very likely considering the nature of the pathology.…”

mentioning

confidence: 99%

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Tendon degeneration is not mediated by regulation of Toll‐like receptors 2 and 4 in human tenocytes

Mos

Joosten

Oppers‐Walgreen

et al. 2009

Journal Orthopaedic Research

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We hypothesized that expression of Toll-like receptors (TLRs) 2 and 4 by tenocytes is involved in the catabolic processes of tendon degeneration. We investigated TLR2 and TLR4 expression by tenocytes in healthy and tendinotic Achilles tendons. We also investigated whether TLR2 and TLR4 could be upregulated in tendon explants using proinflammatory cytokines interleukin (IL)-1b and tumor necrosis factor alphpa (TNFa). Peroperatively harvested healthy (n ¼ 5) and tendinotic (n ¼ 13) Achilles tendon samples were examined by real-time RT-PCR and immunohistochemical staining for TLR2 and TLR4. In addition, the catabolic process in tendinopathy was analyzed by real-time RT-PCR for matrix metalloproteinases MMP1, MMP3, MMP9, and MMP13. Furthermore, healthy tendon explants were cultured in the presence of 20 ng/ml IL-1b (n ¼ 10) or 10 ng/mL TNFa (n ¼ 8) for 4, 24, 48, and 72 h before analysis of TLR and MMP expression levels. Although mRNA levels for both TLR2 and TLR4 were detected in healthy and tendinotic Achilles tendons, we could not confirm expression of these receptors by immunohistochemical staining in either healthy or tendinotic tendon samples. Both receptors did not show significant transcriptional regulation in tendinopathy, although MMP3 was downregulated and MMP9 was upregulated in tendinopathy. In tendon explant cultures TLR2 mRNA was upregulated by TNFa (p < 0.05) and IL-1b (not significant). TLR4 gene expression was not altered by addition of IL-1b or TNFa. Tendon tissue can be stimulated to increase TLR2 gene expression by addition of catabolic factors TNFa or IL-1b. However, the catabolic processes in Achilles tendinopathy cannot be attributed to regulation of TLR2 and TLR4 by tenocytes. Toll-like receptors (TLRs) are phylogenetically conserved transmembrane receptors belonging to the family of pattern-recognition receptors (PRR). In humans, 11 TLR homologs have been identified thus far, expressed by numerous cell types like monocytes and dendritic cells, 1 and for example by chondrocytes. 2 TLRs detect microbial components, but TLR2 and TLR4 also recognize endogenous ligands like heat-shock proteins, necrotic cells, hyaluronan, and fibronectin. 1 Ligand recognition elicits an immune response with upregulation and activation of proinflammatory cytokines and matrix-metalloproteinases (MMPs). 2 Hence, via endogenous ligand recognition the TLR-mediated catabolic signalling pathways can directly contribute to degradative tissue reactions even in the absence of microbial components. TLRs are implicated in inflammatory and autoimmune diseases, but also in disorders like atherosclerosis and cancer. 3,4 Furthermore they play a role in noninfected rheumatoid arthritis (RA) and in the primarily degenerative joint disease osteoarthritis (OA). [1][2][3]5,6 In degenerative tendinopathies the balance between matrix synthesis and degradation is disturbed, and increased MMP activity as well as an increased percentage of degraded collagen are found. 7-9 An increase in NO synthase expression was found in a sup...

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Engineering Inflammation‐Resistant Cartilage: Bridging Gene Therapy and Tissue Engineering

Bonato

Fisch

Ponta

et al. 2023

Adv Healthcare Materials

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Articular cartilage defects caused by traumatic injury rarely heal spontaneously and predispose into post-traumatic osteoarthritis. In the current autologous cell-based treatments the regenerative process is often hampered by the poor regenerative capacity of adult cells and the inflammatory state of the injured joint. The lack of ideal treatment options for cartilage injuries motivated the authors to tissue engineer a cartilage tissue which would be more resistant to inflammation. A clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout of TGF-𝜷-activated kinase 1 (TAK1) gene in polydactyly chondrocytes provides multivalent protection against the signals that activate the pro-inflammatory and catabolic NF-𝜿B pathway. The TAK1-KO chondrocytes encapsulate into a hyaluronan hydrogel deposit copious cartilage extracellular matrix proteins and facilitate integration onto native cartilage, even under proinflammatory conditions. Furthermore, when implanted in vivo, compared to WT fewer pro-inflammatory M1 macrophages invade the cartilage, likely due to the lower levels of cytokines secreted by the TAK1-KO polydactyly chondrocytes. The engineered cartilage thus represents a new paradigm-shift for the creation of more potent and functional tissues for use in regenerative medicine.

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The catabolic pathway mediated by Toll‐like receptors in human osteoarthritic chondrocytes

Cited by 245 publications

References 32 publications

Shift from toll‐like receptor 2 (TLR‐2) toward TLR‐4 dependency in the erosive stage of chronic streptococcal cell wall arthritis coincident with TLR‐4–mediated interleukin‐17 production

Shift from toll‐like receptor 2 (TLR‐2) toward TLR‐4 dependency in the erosive stage of chronic streptococcal cell wall arthritis coincident with TLR‐4–mediated interleukin‐17 production

Tendon degeneration is not mediated by regulation of Toll‐like receptors 2 and 4 in human tenocytes

Engineering Inflammation‐Resistant Cartilage: Bridging Gene Therapy and Tissue Engineering

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