title: γ-Glutamyltranspeptidase is an endogenous activator of Toll-like receptor 4-mediated osteoclastogenesis.
abstract: Chronic inflammation-associated bone destruction, which is observed in rheumatoid arthritis (RA) and periodontitis, is mediated by excessive osteoclastogenesis. We showed previously that γ-glutamyltranspeptidase (GGT), an enzyme involved in glutathione metabolism, acts as an endogenous activator of such pathological osteoclastogenesis, independent of its enzymatic activity. GGT accumulation is clinically observed in the joints of RA patients, and, in animals, the administration of recombinant GGT to the gingival sulcus as an in vivo periodontitis model induces an increase in the number of osteoclasts. However, the underlying mechanisms of this process remain unclear. Here, we report that Toll-like receptor 4 (TLR4) recognizes GGT to activate inflammation-associated osteoclastogenesis. Unlike lipopolysaccharide, GGT is sensitive to proteinase K treatment and insensitive to polymyxin B treatment. TLR4 deficiency abrogates GGT-induced osteoclastogenesis and activation of NF-κB and MAPK signaling in precursor cells. Additionally, GGT does not induce osteoclastogenesis in cells lacking the signaling adaptor MyD88. The administration of GGT to the gingival sulcus induces increased osteoclastogenesis in wild-type mice, but does not induce it in TLR4-deficient mice. Our findings elucidate a novel mechanism of inflammation-associated osteoclastogenesis, which involves TLR4 recognition of GGT and subsequent activation of MyD88-dependent signaling.
authors: Biobank, Medical Genome Center, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan.
authors: Sawako
authors: S
authors: Moriwaki
authors: Department of Oral Microbiology, Division of Oral Infections and Health Sciences, Asahi University School of Dentistry, Mizuho 501-0296, Japan.
authors: Takeshi
authors: T
authors: Into
authors: Department of Pharmacology, School of Dentistry, Showa University, Tokyo 142-8555, Japan.
authors: Keiko
authors: K
authors: Suzuki
authors: Department of Oral and Maxillofacial Pathology, Institute of Biomedical &Health Sciences, Hiroshima University, Hiroshima 734-8522, Japan.
authors: Mutsumi
authors: M
authors: Miyauchi
authors: Department of Oral and Maxillofacial Pathology, Institute of Biomedical &Health Sciences, Hiroshima University, Hiroshima 734-8522, Japan.
authors: Takashi
authors: T
authors: Takata
authors: Department of Bacteriology II, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
authors: Keigo
authors: K
authors: Shibayama
authors: Biobank, Medical Genome Center, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan.
authors: Shumpei
authors: S
authors: Niida
mesh_terms: D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010012:Osteogenesis; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D005723:gamma-Glutamyltransferase; D020928:Mitogen-Activated Protein Kinases