Long non‑coding RNA XIST inhibits osteoblast differentiation and promotes osteoporosis via Nrf2 hyperactivation by targeting CUL3

Abstract

Osteoporosis (OP) is a common skeletal disorder characterized by a low bone mass and the deterioration of bone structure. Long non-coding (lnc)RNA X inactive-specific transcript (XIST) is highly expressed in the serum and monocytes of patients with OP. Thus, the purpose of the present study was to explore the mechanisms underlying the role of XIST in the progression of OP. To establish animal models of OP, female rats underwent a bilateral ovariectomy. The bone mineral density of individual rats was measured using dual-energy X-ray absorptiometry. The combination of XIST and cullin-3 (CUL3) was analyzed using a dual-luciferase reporter assay. Bone histopathological changes were assessed by hematoxylin and eosin staining. Alkaline phosphatase activity was examined by ALP staining. Finally, a series of functional experiments were performed to examine the effects of XIST on cellular behaviors. In the present study, XIST promoted OP and inhibited bone formation by regulating the expression levels of CUL3 and nuclear factor erythroid 2-related factor 2 (Nrf2) in the rats with OP. Moreover, XIST directly targeted CUL3 and negatively regulated its expression. Of note, CUL3 downregulation reversed the effects of XIST silencing on cell viability, differentiation and mineralization, as well as the expression of Nrf2 and CUL3 in MC3T3-E1 cells. Collectively, XIST was demonstrated to inhibit the differentiation of osteoblasts and promote OP by inhibiting the degradation of Nrf2 via targeting CUL3.

Identification of key genes and biological pathways in chronic obstructive pulmonary disease using bioinformatics and next generation sequencing data analysis

“…EGR1 [92], ATF3 [93], XIST (X inactive specific transcript) [94], S100A12 [95] and S100A8 [96] were identified as a candidate genes of heart problems. EGR1 [97], ATF3 [63] and XIST (X inactive specific transcript) [98] are involved in the development of osteoporosis. A recent research suggested that EGR1 [99] and S100A8 [100] contributed to the advancement of depression and anxiety.…”

Bioinformatics identification and experimental validation of m6A-related diagnostic biomarkers in the subtype classification of blood monocytes from postmenopausal osteoporosis patients

“…Existing studies have confirmed that RBM15 in stress hematopoiesis have a variety of aging-related physiologic changes, including increased DNA damage and NF-κB activation ( 53 ), which may serve as important pathological factors in the development of osteoporosis. In addition, study has reported that knockdown of RBM15 and RBM15B impairs XIST-mediated gene silencing ( 52 ), which influences osteoblast differentiation in osteoporosis ( 54 ). Therefore, to our knowledge, the seven candidate m6A modulators may play an important part in the occurrence and development of osteoporosis according to previous studies.…”

Three Classes of Antioxidant Defense Systems and the Development of Postmenopausal Osteoporosis

“…It has also been demonstrated that the activation of Nrf2 promotes osteogenic differentiation by increasing heme oxygenase-1 (HO-1) expression ( Liu et al, 2018 ; Chen et al, 2020b ). However, it is worth noting that the overexpression of Nrf2 might inhibit the differentiation of osteoblasts ( Chen et al, 2021b ). GSH inhibits the osteoclast differentiation-mediated NF-κB signaling pathway induced by ROS ( Han et al, 2020 ).…”