Tryptase β regulation of joint lubrication and inflammation via proteoglycan-4 in osteoarthritis

• Published in: Nature communications Vol. 14; no. 1; pp. 1910 - 20
• Main Authors: Das, Nabangshu, de Almeida, Luiz G. N., Derakhshani, Afshin, Young, Daniel, Mehdinejadiani, Kobra, Salo, Paul, Rezansoff, Alexander, Jay, Gregory D., Sommerhoff, Christian P., Schmidt, Tannin A., Krawetz, Roman, Dufour, Antoine
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.04.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/51; 631/45/468; 631/45/474; 631/553/2710; 692/4023; 82/1; 82/29; 82/58; Animals; Anti-inflammatory agents; Arthritis; Cartilage; Cartilage diseases; Cartilage, Articular - metabolism; Destabilization; Electrophoresis; Extracellular matrix; Fibroblasts; Gel electrophoresis; Homeostasis; Humanities and Social Sciences; Humans; Inflammation - metabolism; Inflammatory diseases; Joints (anatomy); Lubrication; Male; Males; Mass spectrometry; Mass spectroscopy; Matrix protein; Meniscus; multidisciplinary; NF-kappa B - metabolism; NF-κB protein; Osteoarthritis; Osteoarthritis - metabolism; Proteins; Proteoglycans; Proteoglycans - metabolism; Proteomes; Proteomics; Rats; Reduction; Science; Science (multidisciplinary); Shotguns; TLR2 protein; Toll-like receptors; Tryptase; Tryptases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37598-3

PRG4 is an extracellular matrix protein that maintains homeostasis through its boundary lubricating and anti-inflammatory properties. Altered expression and function of PRG4 have been associated with joint inflammatory diseases, including osteoarthritis. Here we show that mast cell tryptase β cleaves PRG4 in a dose- and time-dependent manner, which was confirmed by silver stain gel electrophoresis and mass spectrometry. Tryptase-treated PRG4 results in a reduction of lubrication. Compared to full-length, cleaved PRG4 further activates NF-κB expression in cells overexpressing TLR2, −4, and −5. In the destabilization of the medial meniscus model of osteoarthritis in rat, tryptase β and PRG4 colocalize at the site of injury in knee cartilage and is associated with disease severity. When human primary synovial fibroblasts from male osteoarthritis patients or male healthy subjects treated with tryptase β and/or PRG4 are subjected to a quantitative shotgun proteomics and proteome changes are characterized, it further supports the role of NF-κB activation. Here we show that tryptase β as a modulator of joint lubrication in osteoarthritis via the cleavage of PRG4. Altered expression and function of the extracellular matrix protein PRG4 have been associated with osteoarthritis. Here, the authors show that mast cell tryptase β cleaves PRG4, resulting in a reduction of lubrication and activation of inflammation in this context.