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1.
JCI Insight ; 4(18)2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31534047

RESUMO

Osteoarthritis (OA) is the leading cause of joint failure, yet the underlying mechanisms remain elusive, and no approved therapies that slow progression exist. Dysregulated integrin function was previously implicated in OA pathogenesis. However, the roles of integrin αVß3 and the integrin-associated receptor CD47 in OA remain largely unknown. Here, transcriptomic and proteomic analyses of human and murine osteoarthritic tissues revealed dysregulated expression of αVß3, CD47, and their ligands. Using genetically deficient mice and pharmacologic inhibitors, we showed that αVß3, CD47, and the downstream signaling molecules Fyn and FAK are crucial to OA pathogenesis. MicroPET/CT imaging of a mouse model showed elevated ligand-binding capacities of integrin αVß3 and CD47 in osteoarthritic joints. Further, our in vitro studies demonstrated that chondrocyte breakdown products, derived from articular cartilage of individuals with OA, induced αVß3/CD47-dependent expression of inflammatory and degradative mediators, and revealed the downstream signaling network. Our findings identify a central role for dysregulated αVß3 and CD47 signaling in OA pathogenesis and suggest that activation of αVß3 and CD47 signaling in many articular cell types contributes to inflammation and joint destruction in OA. Thus, the data presented here provide a rationale for targeting αVß3, CD47, and their signaling pathways as a disease-modifying therapy.


Assuntos
Antígeno CD47/metabolismo , Cartilagem Articular/patologia , Integrina alfaVbeta3/metabolismo , Osteoartrite/imunologia , Transdução de Sinais/imunologia , Animais , Antígeno CD47/genética , Antígeno CD47/imunologia , Cartilagem Articular/citologia , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/imunologia , Células Cultivadas , Condrócitos , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/imunologia , Masculino , Camundongos , Osteoartrite/diagnóstico por imagem , Osteoartrite/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Cultura Primária de Células , Proteômica , Membrana Sinovial/citologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinoviócitos , Microtomografia por Raio-X
2.
Elife ; 82019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31084709

RESUMO

Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice. Using genetic and pharmacologic approaches, we show that the IgE/FcεRI/Syk signaling axis is critical for the development of osteoarthritis. We find that mast cell-derived tryptase induces inflammation, chondrocyte apoptosis, and cartilage breakdown. Our findings demonstrate a central role for IgE-dependent mast cell activation in the pathogenesis of osteoarthritis, suggesting that targeting mast cells could provide therapeutic benefit in human osteoarthritis. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).


Assuntos
Cartilagem/patologia , Imunoglobulina E/metabolismo , Fatores Imunológicos/metabolismo , Mastócitos/imunologia , Osteoartrite/patologia , Animais , Perfilação da Expressão Gênica , Humanos , Camundongos , Microscopia Eletrônica , Proteômica , Transdução de Sinais
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