Chondrocyte innate immune myeloid differentiation factor 88–dependent signaling drives procatabolic effects of the endogenous toll‐like receptor 2/toll‐like receptor 4 ligands low molecular weight hyaluronan and high mobility group box chromosomal protein 1 in mice

Liu‐Bryan, Ru; Terkeltaub, Robert

doi:10.1002/art.27475

Cited by 117 publications

(65 citation statements)

References 52 publications

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“…TLR-4 gene expression was increased in the synovial tissue of stifle joints with OA induced by cranial cruciate ligament transection in dogs, but expression of TLR-2 remained unchanged [154]. MyD88 dependent TLR2/TLR4 signaling was demonstrated as crucial in mediating catabolic responses to low molecular weight hyaluronan (LMW-HA) and HMG-B1 in murine cartilage explants [155]. Alarmins S100A8 and S100A9 were shown to induce cartilage catabolism in human OA chondrocytes by activating TLR-4 [156].…”

Section: Major Signaling Pathways Involved In Oamentioning

confidence: 99%

Immunopathogenesis of osteoarthritis

Haseeb

Haqqi

2013

Clinical Immunology

350

295

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Even though osteoarthritis (OA) is mainly considered as a degradative condition of the articular cartilage, there is increasing body of data demonstrating the involvement of all branches of the immune system. Genetic, metabolic or mechanical factors cause an initial injury to the cartilage resulting in release of several cartilage specific auto-antigens, which trigger the activation of immune response. Immune cells including T cells, B cells and macrophages infiltrate the joint tissues, cytokines and chemokines are released from different kind of cells present in the joint, complement system is activated, cartilage degrading factors such as matrix metalloproteins (MMPs) and prostaglanding E2 (PGE2) are released, resulting in further damage to the articular cartilage. There is considerable success in the treatment of rheumatoid arthritis using anti-cytokine therapies. In OA, however, these therapies did not show much effect, highlighting more complex nature of pathogenesis of OA. This needs the development of more novel approaches to treat OA, which may include therapies that act on multiple targets. Plant natural products have this kind of properties and may be considered for future drug development efforts. Here we reviewed the studies implicating different components of the immune system in the pathogenesis of OA.

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Section: Major Signaling Pathways Involved In Oamentioning

confidence: 99%

Immunopathogenesis of osteoarthritis

Haseeb

Haqqi

2013

Clinical Immunology

350

295

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“…Moreover, Toll-like receptor 2 (TLR-2) and TLR-4, in addition to mediating innate immune responses to pathogens, are also responsible for orchestrating chronic inflammatory and tissue remodeling to endogenous ligands; and their expression is elevated in OA cartilage and induced by IL-1β and TNFα (Kim et al , 2006; Bobacz et al , 2007). Recently, two endogenous shared TLR-2/TLR-4 ligands, low molecular weight hyaluronan (LMW-HA) and high mobility group box chromosomal protein 1 (HMGB-1), which are increased in OA joints, were shown to promote MMP-13 mediated ECM remodeling and chondrocyte differentiation towards hypertrophy by engaging TLR-dependent, MyD88 (myeloid differentiation factor 88) signaling leading to the activation of NF-κB dependent genes including MMP-13 (Liu-Bryan and Terkeltaub, 2010). …”

Section: Signaling and Transcriptional Regulation Of Chondrocyte Catamentioning

confidence: 99%

Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis

Goldring

Otero

Plumb

et al. 2011

eCM

399

330

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Human cartilage is a complex tissue of matrix proteins that vary in amount and orientation from superficial to deep layers and from loaded to unloaded zones. A major challenge to efforts to repair cartilage by stem cell-based and other tissue engineering strategies is the inability of the resident chondrocytes to lay down new matrix with the same structural and resilient properties that it had upon its original formation. This is particularly true for the collagen network, which is susceptible to cleavage once proteoglycans are depleted. Thus, a thorough understanding of the similarities and particularly the marked differences in mechanisms of cartilage remodeling during development, osteoarthritis, and aging may lead to more effective strategies for preventing cartilage damage and promoting repair. To identify and characterize effectors or regulators of cartilage remodeling in these processes, we are using culture models of primary human and mouse chondrocytes and cell lines and mouse genetic models to manipulate gene expression programs leading to matrix remodeling and subsequent chondrocyte hypertrophic differentiation, pivotal processes which both go astray in OA disease. Matrix metalloproteinase (MMP)-13, the major type II collagen-degrading collagenase, is regulated by stress-, inflammation-, and differentiation-induced signals that not only contribute to irreversible joint damage (progression) in OA, but importantly, also to the initiation/onset phase, wherein chondrocytes in articular cartilage leave their natural growth-and differentiation-arrested state. Our work points to common mediators of these processes in human OA cartilage and in early through late stages of OA in surgical and genetic mouse models.

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“…(b) Intracellular alarmins: Intracellular proteins released from stressed, damaged or necrotic cells, sequestered within cell, can signal to immune system [56] e.g. High mobility group box1 protein (HMGB-1) [57] and S-100 family of proteins (S100 A8 & S100 A9 in synovium) [58,59]. These proteins upregulate catabolic mediators including MMPs 1, 3, 9 & 13 as well as cytokines IL-6 and concomitant down-regulation of aggrecan and type-2 collagen [60].…”

Section: Mechanism Of Inflammation In Oamentioning

confidence: 99%

Chondroitin sulphate: a focus on osteoarthritis

et al. 2016

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Chondroitin sulfate (CS) being a natural glycosaminoglycan is found in the cartilage and extracellular matrix. It shows clinical benefits in symptomatic osteoarthritis (OA) of the finger, knee, hip joints, low back, facial joints and other diseases due to its anti-inflammatory activity. It also helps in OA by providing resistance to compression, maintaining the structural integrity, homeostasis, slows breakdown and reduces pain in sore muscles. It is most often used in combination with glucosamine to treat OA. CS is a key role player in the regulation of cell development, cell adhesion, proliferation, and differentiation. Its commercial applications have been continuously explored in the engineering of biological tissues and its combination with other biopolymers to formulate scaffolds which promote and accelerate the regeneration of damaged structure. It is approved in the USA as a dietary supplement for OA, while it is used as a symptomatic slow-acting drug (SYSADOA) in Europe and some other countries. Any significant side effects or overdoses of CS have not been reported in clinical trials suggesting its long-term safety. This review highlights the potential of CS, either alone or in combination with other drugs, to attract the scientists engaged in OA treatment and management across the world.

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Chondrocyte innate immune myeloid differentiation factor 88–dependent signaling drives procatabolic effects of the endogenous toll‐like receptor 2/toll‐like receptor 4 ligands low molecular weight hyaluronan and high mobility group box chromosomal protein 1 in mice

Cited by 117 publications

References 52 publications

Immunopathogenesis of osteoarthritis

Immunopathogenesis of osteoarthritis

Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis

Chondroitin sulphate: a focus on osteoarthritis

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