Cyclin G2 Suppresses Estrogen-Mediated Osteogenesis through Inhibition of Wnt/β-Catenin Signaling

Abstract

Estrogen plays an important role in the maintenance of bone formation, and deficiency in the production of estrogen is directly linked to postmenopausal osteoporosis. To date, the underlying mechanisms of estrogen-mediated osteogenic differentiation are not well understood. In this study, a pluripotent mesenchymal precursor cell line C2C12 was used to induce osteogenic differentiation and subjected to detection of gene expressions or to manipulation of cyclin G2 expressions. C57BL/6 mice were used to generate bilateral ovariectomized and sham-operated mice for analysis of bone mineral density and protein expression. We identified cyclin G2, an unconventional member of cyclin, is involved in osteoblast differentiation regulated by estrogen in vivo and in vitro. In addition, the data showed that ectopic expression of cyclin G2 suppressed expression of osteoblast transcription factor Runx2 and osteogenic differentiation marker genes, as well as ALP activity and in vitro extracellular matrix mineralization. Mechanistically, Wnt/β-catenin signaling pathway is essential for cyclin G2 to inhibit osteogenic differentiation. To the best of our knowledge, the current study presents the first evidence that cyclin G2 serves as a negative regulator of both osteogenesis and Wnt/β-catenin signaling. Most importantly, the basal and 17β-estradiol-induced osteogenic differentiation was restored by overexpression of cyclin G2. These results taken together suggest that cyclin G2 may function as an endogenous suppressor of estrogen-induced osteogenic differentiation through inhibition of Wnt/β-catenin signaling.

Cyclin G2 Inhibits the Warburg Effect and Tumour Progression by Suppressing LDHA Phosphorylation in Glioma

“…Apart from its critical role in glycolysis, LDHA also facilitates tumour progression, including glioma 39. To verify an interaction between cyclin G2 and LDHA, cyclin G2 was overexpressed in U87 and U251 as previous described 40. Co-immunoprecipitation confirmed that cyclin G2 formed a complex with LDHA (Figure 4b).…”

The Role of Macrophage in the Pathogenesis of Osteoporosis

“…Estrogen may induce osteoblast differentiation in bone formation by binding the estrogen receptor through the upregulation of PACE4 expression [51], and it also has an anabolic effect on the function of osteoblasts [52]. Estrogen serves different biological functions in the regulation of osteogenic differentiation with involvement of the Wnt/β-catenin signaling pathway [53]. Estrogen loss may also influence the immune system through upregulation of T and B cells [54].…”

Cyclin G2 Suppresses Glomerulosclerosis by Regulating Canonical Wnt Signalling

“…Recent studies suggested that cyclin G2 could inhibit canonical Wnt signalling in bone metabolism and epithelial ovarian cancer [ 13 , 14 ]. In this study, overexpression of cyclin G2 in HMC cells resulted in the negative regulation of proteins involved in canonical Wnt signalling and suppressed the high-glucose–induced upregulation of these proteins.…”

“…Recent findings have demonstrated that cyclin G2 has potent tumour-suppressive activity in epithelial ovarian cancer by inhibiting EMT through the attenuation of Wnt signalling [ 13 ]. The results from our preliminary studies suggested that cyclin G2 ( CCNG2 ) could inhibit canonical Wnt signalling and regulate bone metabolism [ 14 ]. However, no evidence has shown whether cyclin G2 specifically functions in the occurrence and development of DN via this pathway.…”