Redox-active endosomes mediate α5β1 integrin signaling and promote chondrocyte matrix metalloproteinase production in osteoarthritis.

Autor: Miao MZ; Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Curriculum in Oral and Craniofacial Biomedicine, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Cell Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA., Su QP; School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Sydney, NSW 2007, Australia., Cui Y; Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Bahnson EM; Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Li G; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.; eScience Institute, University of Washington, Seattle, WA 98195, USA., Wang M; Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Yang Y; State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-sen University, Guangzhou 510275, China., Collins JA; Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA., Wu D; Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Gu Q; Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China.; Department of Immunology, Université Paris Cité, Paris 75006, France., Chubinskaya S; Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, USA., Diekman BO; Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695, USA., Yamada KM; Cell Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA., Loeser RF; Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2023 Oct 31; Vol. 16 (809), pp. eadf8299. Date of Electronic Publication: 2023 Oct 31.
DOI: 10.1126/scisignal.adf8299
Abstrakt: Mechanical cues sensed by integrins induce cells to produce proteases to remodel the extracellular matrix. Excessive protease production occurs in many degenerative diseases, including osteoarthritis, in which articular cartilage degradation is associated with the genesis of matrix protein fragments that can activate integrins. We investigated the mechanisms by which integrin signals may promote protease production in response to matrix changes in osteoarthritis. Using a fragment of the matrix protein fibronectin (FN) to activate the α5β1 integrin in primary human chondrocytes, we found that endocytosis of the integrin and FN fragment complex drove the production of the matrix metalloproteinase MMP-13. Activation of α5β1 by the FN fragment, but not by intact FN, was accompanied by reactive oxygen species (ROS) production initially at the cell surface, then in early endosomes. These ROS-producing endosomes (called redoxosomes) contained the integrin-FN fragment complex, the ROS-producing enzyme NADPH oxidase 2 (NOX2), and SRC, a redox-regulated kinase that promotes MMP-13 production. In contrast, intact FN was endocytosed and trafficked to recycling endosomes without inducing ROS production. Articular cartilage from patients with osteoarthritis showed increased amounts of SRC and the NOX2 complex component p67 phox . Furthermore, we observed enhanced localization of SRC and p67 phox at early endosomes, suggesting that redoxosomes could transmit and sustain integrin signaling in response to matrix damage. This signaling mechanism not only amplifies the production of matrix-degrading proteases but also establishes a self-perpetuating cycle that contributes to the ongoing degradation of cartilage matrix in osteoarthritis.
Databáze: MEDLINE