Iron accumulation regulates osteoblast apoptosis through lncRNAXIST/miR‐758‐3p/caspase 3 axis leading to osteoporosis

Abstract

Postmenopausal osteoporosis (PMOP) is mainly caused by multiple factors. Recent studies have suggested that iron accumulation (IA) was closely related to PMOP. However, the detailed molecular mechanisms have not been well demonstrated. We constructed the IA mouse model by intraperitoneal injections of ferric ammonium citrate (FAC) and cell model by culturing with the medium containing FAC. Osteoporosis was confirmed in mouse bone tissues using H&E staining, and the level of serum ferritin, alkaline phosphatase (ALP), procollagen-1 N-terminal peptide (P1NP), and osteocalcin in mice was examined by ELISA. The expressions of XIST and miR-758-3p were detected by qRT-PCR. Cell proliferation and apoptosis were measured by CCK-8, TUNEL, and flow cytometry. The expression levels of apoptotic-related proteins were evaluated by western blot. Dual luciferase reporter assay was used to examine the molecular interaction. The expressions of ALP, P1NP, and osteocalcin, and the H&E staining of bone tissues in mice were analyzed to confirm the biological function of XIST and miR-758-3p in vivo. XIST was up-regulated while miR-758-3p was down-regulated in IA mouse and cell models. XIST knockdown significantly reduced FAC-induced osteoblast apoptosis, which was mimicked by transfection with miR-758-3p mimics. XIST acted as a sponge of miR-758-3p, which targeted caspase 3. IA led to the high expression of XIST and promoted osteoblast apoptosis through miR-758-3p/caspase 3. Transfection with shXIST or miR-758-3p mimics alleviated IA-induced mouse osteoporosis. IA regulated osteoblast apoptosis through XIST/miR-758-3p/caspase 3 axis, which might provide alternative targets for the treatment of osteoporosis.

Long non-coding RNA XIST promotes osteoporosis by inhibiting the differentiation of bone marrow mesenchymal stem cell by sponging miR-29b-3p that suppresses nicotinamide N-methyltransferase

“…Previous studies have demonstrated that XIST participates in the OP [ 14 , 19 , 20 ]. Here, we found that XIST is upregulated in the patients of OP.…”

Iron overload‐induced ferroptosis of osteoblasts inhibits osteogenesis and promotes osteoporosis: An in vitro and in vivo study

“…The optical density of each well was measured at 450 nm using a microplate reader (Epoch; BioTek Instruments, Inc., USA). FAC concentration range was chosen based on the preliminary investigations and previously reported studies 26–29 …”

Effects of miRNAs, lncRNAs and circRNAs on osteoporosis as regulatory factors of bone homeostasis (Review)

“…recent results have shown that iron accumulation (ia), which is a pathological risk factor among postmenopausal women, is related to postmenopausal osteoporosis and that iron accumulation leads to BMSc apoptosis by activating the caspase 3 pathway. The latest study reported that the expression of the lncrna XiST was increased in ia mouse and cell models, indicating that XiST may play an important role in osteoporosis (120). Furthermore, knockdown of XiST can suppress oB apoptosis induced by ia via the regulation of caspase 3.…”