IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis

Wang, Qian; Lepus, Christin M.; Raghu, Harini; Reber, Laurent L.; Tsai, Mindy; Wong, Heidi; Kaeppler, Ericka von; Lingampalli, Nithya; Bloom, Michelle S.; Hu, Nick; Elliott, Eileen E; Oliviero, Francesca; Punzi, Leonardo; Giori, Nicholas J.; Goodman, Stuart B.; Chu, Constance R.; Sokolove, Jeremy; Fukuoka, Yoshihiro; Schwartz, Lawrence B.; Galli, Stephen J.; Robinson, William H.

doi:10.7554/elife.39905

Cited by 95 publications

(112 citation statements)

References 70 publications

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“…Furthermore, the inhibition of tryptase activity in wildtype mice prevented OA and reduced the concentrations of the pro-inflammatory and proteolytic mediators, e.g., IL-6, IL-1β, IL-8, and MMP-3. The authors further showed that in OA, MCs are activated via the IgE/FcεRI receptor axis (196). Another study showed that synovial MCs from OA patients produce TNF-α upon stimulation via the high-affinity receptor for IgG (174).…”

Section: Rheumatoid Arthritismentioning

confidence: 96%

“…Interestingly, it has been shown that MCs may also play a role in OA, in which joint destruction is mainly caused by degeneration, abnormal high loads, or traumatic injuries (190), and driven by an increased inflammatory response (191). Several clinical studies reported increased MC numbers in the synovial tissue of OA patients and/or elevated histamine or tryptase levels in the synovial fluid (7,(192)(193)(194)(195)(196). Gene cluster analysis revealed increased expression of genes involved in MC differentiation and activity (c-KIT, tryptase genes TPSAB1, and TPSAB2) in the synovial membranes of OA patients (196).…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

“…Several clinical studies reported increased MC numbers in the synovial tissue of OA patients and/or elevated histamine or tryptase levels in the synovial fluid (7,(192)(193)(194)(195)(196). Gene cluster analysis revealed increased expression of genes involved in MC differentiation and activity (c-KIT, tryptase genes TPSAB1, and TPSAB2) in the synovial membranes of OA patients (196). Interestingly, two different MC-deficient mouse lines, the c-Kitdependent Kit W−sh/W−sh line and the Kit-independent Cpa3 Cre ; Mcl-1 fl/fl mice, were protected from OA as demonstrated by reduced inflammation and cartilage destruction, while MC engraftment reversed the protective effects in both mouse lines (196).…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

“…Gene cluster analysis revealed increased expression of genes involved in MC differentiation and activity (c-KIT, tryptase genes TPSAB1, and TPSAB2) in the synovial membranes of OA patients (196). Interestingly, two different MC-deficient mouse lines, the c-Kitdependent Kit W−sh/W−sh line and the Kit-independent Cpa3 Cre ; Mcl-1 fl/fl mice, were protected from OA as demonstrated by reduced inflammation and cartilage destruction, while MC engraftment reversed the protective effects in both mouse lines (196). Furthermore, the inhibition of tryptase activity in wildtype mice prevented OA and reduced the concentrations of the pro-inflammatory and proteolytic mediators, e.g., IL-6, IL-1β, IL-8, and MMP-3.…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

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The Role of Mast Cells in Bone Metabolism and Bone Disorders

et al. 2020

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Mast cells (MCs) are important sensor and effector cells of the immune system that are involved in many physiological and pathological conditions. Increasing evidence suggests that they also play an important role in bone metabolism and bone disorders. MCs are located in the bone marrow and secrete a wide spectrum of mediators, which can be rapidly released upon activation of mature MCs following their differentiation in mucosal or connective tissues. Many of these mediators can exert osteocatabolic effects by promoting osteoclast formation [e.g., histamine, tumor necrosis factor (TNF), interleukin-6 (IL-6)] and/or by inhibiting osteoblast activity (e.g., IL-1, TNF). By contrast, MCs could potentially act in an osteoprotective manner by stimulating osteoblasts (e.g., transforming growth factor-β) or reducing osteoclastogenesis (e.g., IL-12, interferon-γ). Experimental studies investigating MC functions in physiological bone turnover using MC-deficient mouse lines give contradictory results, reporting delayed or increased bone turnover or no influence depending on the mouse model used. By contrast, the involvement of MCs in various pathological conditions affecting bone is evident. MCs may contribute to the pathogenesis of primary and secondary osteoporosis as well as inflammatory disorders, including rheumatoid arthritis and osteoarthritis, because increased numbers of MCs were found in patients suffering from these diseases. The clinical observations could be largely confirmed in experimental studies using MC-deficient mouse models, which also provide mechanistic insights. MCs also regulate bone healing after fracture by influencing the inflammatory response toward the fracture, vascularization, bone formation, and callus remodeling by osteoclasts. This review summarizes the current view and understanding of the role of MCs on bone in both physiological and pathological conditions.

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Section: Rheumatoid Arthritismentioning

confidence: 96%

Section: Rheumatoid Arthritismentioning

confidence: 99%

Section: Rheumatoid Arthritismentioning

confidence: 99%

Section: Rheumatoid Arthritismentioning

confidence: 99%

See 2 more Smart Citations

The Role of Mast Cells in Bone Metabolism and Bone Disorders

et al. 2020

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“… 62 The same research group also identified mast-cell activity as a pathogenic mediator in murine osteoarthritis. 76 Mast-cell activation has previously been described in the osteoarthritis joint, 81 and is associated with structural disease. 25 …”

Section: Targeting Inflammation In Osteoarthritismentioning

confidence: 98%

Of mice and men: converging on a common molecular understanding of osteoarthritis

Vincent

2020

The Lancet Rheumatology

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Despite an increasing burden of osteoarthritis in developed societies, target discovery has been slow and there are currently no approved disease-modifying osteoarthritis drugs. This lack of progress is due in part to a series of misconceptions over the years: that osteoarthritis is an inevitable consequence of ageing, that damaged articular cartilage cannot heal itself, and that osteoarthritis is driven by synovial inflammation similar to that seen in rheumatoid arthritis. Molecular interrogation of disease through ex-vivo tissue analysis, in-vitro studies, and preclinical models have radically reshaped the knowledge landscape. Inflammation in osteoarthritis appears to be distinct from that seen in rheumatoid arthritis. Recent randomised controlled trials, using treatments repurposed from rheumatoid arthritis, have largely been unsuccessful. Genome-wide studies point to defects in repair pathways, which accords well with recent promise using growth factor therapies or Wnt pathway antagonism. Nerve growth factor has emerged as a robust target in osteoarthritis pain in phase 2–3 trials. These studies, both positive and negative, align well with those in preclinical surgical models of osteoarthritis, indicating that pathogenic mechanisms identified in mice can lead researchers to valid human targets. Several novel candidate pathways are emerging from preclinical studies that offer hope of future translational impact. Enhancing trust between industry, basic, and clinical scientists will optimise our collective chance of success.

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Salvinorin A inhibits ovalbumin‐stimulated allergic rhinitis and RBL‐2H3 cells degranulation

2021

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Allergic rhinitis is a long-term noncommunicable inflammatory disease of the nasal mucosa mediated by IgE and is mainly caused by exposure of genetically susceptible individuals to environmental allergens. Mast cells contribute to the pathogenesis of allergic and nonallergic inflammatory diseases. Salvinorin A has been previously shown to inhibit leukotriene (LT) production and mast cell degranulation to suppress airway hyperresponsiveness caused by sensitization, and thus, we hypothesized that salvinorin A has an anti-allergic rhinitis effect. We tested this hypothesis using monoclonal anti-2,4,6-dinitrophenyl immunoglobulin (Ig) E/human serum albumin (DNP-IgE/HSA)-induced rat basophilic leukemia cells (RBL-2H3 cells) and ovalbumin (OVA)-induced allergic rhinitis (AR) in mice as in vivo and in vitro AR models, respectively. The expression levels of histamine, β-hexosaminidase, interleukin (IL)-4, and tumor necrosis factor (TNF)-α were decreased by salvinorin A in vitro. Granule release and F-actin organization were also suppressed by salvinorin A. Furthermore, salvinorin A inhibited OVA-induced features of allergic rhinitis in mice, including nasal rubbing and sneezing, as well as increased OVA-specific IgE, histamine, TNF-α and IL-4 levels. Additionally, salvinorin A decreased the phosphorylation of phosphoinositide 3-kinase (PI3K)/Akt in vitro and in vivo. Our work suggests that salvinorin A suppresses allergic rhinitis caused by sensitization by inhibiting the inflammatory responses of mast cells, and thus salvinorin A may have potential for treatment of allergic rhinitis.

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IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis

Cited by 95 publications

References 70 publications

The Role of Mast Cells in Bone Metabolism and Bone Disorders

The Role of Mast Cells in Bone Metabolism and Bone Disorders

Of mice and men: converging on a common molecular understanding of osteoarthritis

Salvinorin A inhibits ovalbumin‐stimulated allergic rhinitis and RBL‐2H3 cells degranulation

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