title: Experimental Arthritis Is Dependent on Mouse Mast Cell Protease-5.
abstract: The constitutive heparin+(HP) mast cells (MCs) in mice express mouse MC protease (mMCP)-5 and carboxypeptidase A (mMC-CPA). The amino acid sequence of mMCP-5 is most similar to that of human chymase-1, as are the nucleotide sequences of their genes and transcripts. Using a homologous recombination approach, a C57BL/6 mouse line was created that possessed a disruptedmMCP-5gene. The resulting mice were fertile and had no obvious developmental abnormality. Lack of mMCP-5 protein did not alter the granulation of the IL-3/IL-9-dependent mMCP-2+MCs in the jejunal mucosa ofTrichinella spiralis-infected mice. In contrast, the constitutive HP+MCs in the tongues of mMCP-5-null mice were poorly granulated and lacked mMC-CPA protein. Bone marrow-derived MCs were readily developed from the transgenic mice using IL-3. Although these MCs contained high levels of mMC-CPA mRNA, they also lacked the latter exopeptidase. mMCP-5 protein is therefore needed to target translated mMC-CPA to the secretory granule along with HP-containing serglycin proteoglycans. Alternately, mMCP-5 is needed to protect mMC-CPA from autolysis in the cell's granules. Fibronectin was identified as a target of mMCP-5, and the exocytosis of mMCP-5 from the MCs in the mouse's peritoneal cavity resulted in the expression of metalloproteinase protease-9, which has been implicated in arthritis. In support of the latter finding, experimental arthritis was markedly reduced in mMCP-5-null mice relative to wild-type mice in two disease models.
authors.affiliation: From the Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2217, Australia, rstevens@richardstevensphd.org.|the Faculty of Health and Medicine, School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales 2308, Australia.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Stevens
authors.affiliation: the Faculty of Medicine and Health Sciences, Macquarie University, New South Wales 2109, Australia.
authors.forename: H Patrick
authors.initials: HP
authors.lastname: McNeil
authors.affiliation: From the Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2217, Australia.|the Department of Immunology, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo 05508900, Brazil.
authors.forename: Lislaine A
authors.initials: LA
authors.lastname: Wensing
authors.affiliation: the Division of Rheumatology, Seoul Metropolitan Government, Seoul National University (SMG-SNU), Boramae Medical Center, Seoul 07061, Korea.
authors.forename: Kichul
authors.initials: K
authors.lastname: Shin
authors.affiliation: the Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and.
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
authors.affiliation: the Centre for Asthma & Respiratory Disease, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales 2308, Australia.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: From the Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2217, Australia.|the Faculty of Health and Medicine, School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales 2308, Australia.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Krilis
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D043422:Carboxypeptidases A / Q000032:analysis / Q000172:deficiency / Q000378:metabolism; D053818:Chymases / Q000009:adverse effects* / Q000172:deficiency / Q000502:physiology; D006801:Humans; D008407:Mast Cells / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D022142:Secretory Vesicles / Q000378:metabolism
chemical_list: D043422:Carboxypeptidases A; C503326:Cpa3 protein, mouse; C509227:Cma1 protein, mouse; D053818:Chymases
keywords: arthritis; carboxypeptidase; heparin; mast cell; serine protease