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Role of bacterial γ-glutamyltranspeptidase as a novel virulence factor in bone-resorbing pathogenesis.

 Jinmoon Kim  ;  Sungil Jang  ;  Aeryun Kim  ;  Hanfu Su  ;  Niluka Gunawardhana  ;  Yeong-Eui Jeon  ;  Eun Jung Bak  ;  Ji-Hye Kim  ;  Jeong-Heon Cha 
 JOURNAL OF MICROBIOLOGY, Vol.54(5) : 396-402, 2016 
Journal Title
Issue Date
Animals ; Bacillus subtilis/enzymology* ; Bone Marrow Cells/drug effects ; Bone Resorption/chemically induced ; Bone Resorption/microbiology ; Bone Resorption/pathology ; Coculture Techniques ; Cytokines/metabolism ; Mice ; Osteoblasts/drug effects ; Osteoclasts/drug effects ; Osteogenesis/drug effects* ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Recombinant Proteins/pharmacology ; Virulence Factors/genetics ; Virulence Factors/pharmacology ; Virulence Factors/physiology ; gamma-Glutamyltransferase/genetics ; gamma-Glutamyltransferase/pharmacology* ; gamma-Glutamyltransferase/physiology
Bacillus subtilis ; bone resorption ; osteoclastogenesis ; γ-glutamyltranspeptidase
Mammalian γ-glutamyltranspeptidase (GGT) has been identified as a bone-resorbing factor. Since GGT of Bacillus subtilis exhibits similarity in their primary structure and enzymatic characteristics with mammalian GGTs, the bone-resorbing activity of bacterial GGT was examined in this study. Osteoclastogenesis was performed in a co-culture system of mouse calvaria-derived osteoblasts and bone marrow cells. A conditioned medium from GGT-overproducing B. subtilis culture showed significantly higher activity of osteoclast formation than a conditioned medium from wild-type B. subtilis culture. Recombinant GGT (rGGT) of wild-type B. subtilis and an enzymatic activity-defected rGGT of B. subtilis 2288 mutant were expressed in Escherichia coli and purified using His tag. Both purified rGGTs induced similar levels of osteoclastogenesis, suggesting that B. subtilis GGT possesses virulent bone-resorbing activity and its activity is probably independent of its enzymatic activity. Furthermore, a recombinant protein of B. subtilis GGT heavy subunit (Bs rGGT/H) showed strong activity of osteoclastogenesis while the light subunit failed to show strong activity, suggesting that the bone-resorbing activity is mainly located at the heavy subunit. More importantly, the GGT enzymatic activity may not be required for this virulence activity since the light subunit contains the catalytic pocket. In addition, B. subtilis rGGT stimulated mRNA expressions of receptor activator of nuclear factor kappa-B ligand (RANKL) and cyclooxygenase-2 (COX-2), while an osteoprotegerin inhibited the osteoclast formation induced by Bs rGGT/H. This is the first demonstration that bacterial GGT itself is sufficient to act as a bone-resorbing virulence factor via RANKL-dependent pathway. Therefore, it can be hypothesized that GGT of periodontopathic bacteria may play an important role as a virulence factor in bone destruction.
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2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jin Moon(김진문)
Jang, Sungil(장성일) ORCID logo https://orcid.org/0000-0001-6144-6899
Jeon, Yeong Eui(전영의) ORCID logo https://orcid.org/0000-0001-6316-4107
Cha, Jung Heon(차정헌) ORCID logo https://orcid.org/0000-0002-9385-2653
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