γ-Glutamyltranspeptidase Stimulates Receptor Activator of Nuclear Factor-κB Ligand Expression Independent of Its Enzymatic Activity and Serves as a Pathological Bone-resorbing Factor

Abstract

A novel bone-resorbing factor was cloned using an expression cloning technique, which involved a Xenopus oocyte expression system and an assay for osteoclast formation. A candidate clone was isolated from a BW5147 mouse T-lymphoma cell cDNA library. Sequencing analysis identified the factor as ␥-glutamyltranspeptidase (GGT), which is an enzyme involved in glutathione metabolism. The addition of purified GGT protein to mouse bone marrow culture effectively induced formation of osteoclasts. An antibody against GGT inhibited osteoclast formation but not the enzymatic activity. We also demonstrated that an inactive form of GGT, the enzymatic activity of which had been blocked by chemical modification with a specific inhibitor, acivicin, supported osteoclast formation. These results indicate that GGT acts on osteoclast formation independent of its own enzymatic activity. Furthermore, both native GGT and inactive GGT stimulated the expression of the receptor activator of nuclear factor-B ligand (RANKL) mRNA and protein from bone marrow stromal cells. This report is the first demonstration of a novel biological activity of GGT protein in a manner independent of its enzymatic activity.

Associations Between Liver Function, Bone Turnover Biomarkers and Adipokines in Older Patients With Hip Fracture

“…A large longitudinal study (16,036 Korean men aged ≥ 50 years) demonstrated that a higher serum GGT level was associated with increased development of osteoporotic fractures over a mean 3-year follow-up period [50]. Experimental data indicate that both a deficiency and an excess of GGT result in osteoporosis [49,[51][52][53]. GGT in vitro stimulates osteoclast formation (independently of its enzymatic activity) and expression of receptor activator of nuclear factor-kB ligand (RANKL) mRNA and protein from bone marrow stromal cells, and in transgenic mice promotes osteoporosis [51][52][53].…”

“…Experimental data indicate that both a deficiency and an excess of GGT result in osteoporosis [49,[51][52][53]. GGT in vitro stimulates osteoclast formation (independently of its enzymatic activity) and expression of receptor activator of nuclear factor-kB ligand (RANKL) mRNA and protein from bone marrow stromal cells, and in transgenic mice promotes osteoporosis [51][52][53]. It has been proposed that osteopenia/osteoporosis in GGT-deficient (GGT-/+) mice is caused by suppression of bone formation, while excess of GGT results mainly in acceleration of bone resorption [53].…”

SNP detection and comparative linkage mapping of 66 bone-related genes in the pig

“…Gamma glutamyl transferase 1 GGT1 GGT1 is a potential marker for bone resorption. It acts as a pathological bone resorbing factor by stimulating RANK ligand (Asaba et al, 2006;Niida et al, 2004). A disintegrin and metallopeptidase domain 12 ADAM12 Stimulates bone growth in mice by modulating chondrocyte proliferation and maturation through mechanisms probably involving both metalloproteinase and adhesion activities (Kveiborg et al, 2006).…”

A higher serum gamma-glutamyl transferase level could be associated with an increased risk of incident osteoporotic fractures in Korean men aged 50 years or older

“…First, GGT may directly play a pathogenic role in the onset of metabolic bone diseases. A previous in vitro study has shown that GGT stimulates receptor activator of nuclear factor-kappaB ligand expression and effectively induces the formation of osteoclasts, independent of its enzymatic activity [14]. Furthermore, the overexpression of GGT in transgenic mice has been reported to accelerate bone resorption and cause osteoporosis [15].…”