Foxf1 knockdown promotes BMSC osteogenesis in part by activating the Wnt/β-catenin signalling pathway and prevents ovariectomy-induced bone loss

Abstract

Background: Forkhead box protein f1 (Foxf1) is associated with cell differentiation, and may be a key player in bone homoeostasis. However, the effect of Foxf1 on osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) and ovariectomy-induced bone loss, as well as its clinical implications, is unknown. Methods: By quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, we assayed Foxf1 expression in bone tissue, BMSCs, and bone marrow-derived macrophages (BMMs), derived from ovariectomised (OVX) mice, and during osteogenic differentiation and osteoclast differentiation. Using a loss-of-function approach (small interfering RNA [siRNA]-mediated knockdown) in vitro, we examined whether Foxf1 regulates osteoblast differentiation of BMSCs via the Wnt/b-catenin signalling pathway. Furthermore, we assessed the anabolic effect of Foxf1 knockdown (siFoxf1) in OVX mice in vivo. We also assayed the expression of Foxf1 in bone tissue derived from postmenopausal osteoporosis (PMOP) patients and its link with bone mineral density (BMD). Finally, we examined the effect of Foxf1 knockdown on the osteoblastic differentiation of human BMSCs. Findings: Foxf1 expression was significantly increased in bone extract and BMSCs from OVX mice and gradually decreased during osteoblastic differentiation of BMSCs but did not differ significantly in OVX mousederived BMMs or during osteoclast differentiation. In vitro, Foxf1 knockdown markedly increased the expression of osteoblast specific genes, alkaline phosphatase (ALP) activity, and mineralisation. Moreover, siFoxf1 activated the Wnt/b-catenin signalling pathway. The siFoxf1-induced increase in osteogenic differentiation was partly rescued by inhibitor of Wnt signalling (DKK1). In OVX mice, Foxf1 siRNA significantly reduced bone loss by enhancing bone formation. Foxf1 expression levels negatively correlated with reduced bone mass and bone formation in bone tissue from PMOP patients. Finally, Foxf1 knockdown significantly promoted osteogenesis by human BMSCs. Interpretation: Our findings indicate that Foxf1 knockdown promotes BMSC osteogenesis and prevents OVXinduced bone loss. Therefore, Foxf1 has potential as a biomarker of osteogenesis and may be a therapeutic target for PMOP.

Circ-ITCH sponges miR-214 to promote the osteogenic differentiation in osteoporosis via upregulating YAP1

“…Studies have shown that in people with osteoporosis, bone loss is induced by the reduced bone formation and increased bone resorption 4 , 5 . The bone formation could be modulated by many transcription factors and signaling pathways 6 – 8 . Therefore, researching the mechanisms that modulate bone formation will be significant for the treatment of osteoporosis.…”

JKAMP inhibits the osteogenic capacity of adipose-derived stem cells in diabetic osteoporosis by modulating the Wnt signaling pathway through intragenic DNA methylation

“…Ubiquitination and degradation of β-catenin are regulated by the balance of GSK-3β and p-GSK-3β [22]. β-Catenin interacts with TCF/LEF-1 or other transcription coactivators in the nucleus and induces the expression of osteogenesis-related molecules to regulate osteogenesis [24,25,47]. Compared with CON-ASCs, DOP-ASCs exhibited relatively downregulated expression of β-catenin, p-GSK-3β, RUNX2, and OPN.…”

Morusin induces osteogenic differentiation of bone marrow mesenchymal stem cells by canonical Wnt/β-catenin pathway and prevents bone loss in an ovariectomized rat model

“…Wnt/β-catenin signaling pathway is vital for BMSC differentiation and is a significant pathway for promoting new bone formation, inhibiting bone resorption, and maintaining bone mass [23,24]. In the current study, increased expression of β-catenin, lymphoid enhancing factor-1(Lef-1), and dishevelled-1 (Dvl-1) mRNAs were detected in BMSCs treated with Morusin (0-10 μM) on the 3rd, 5th, and 7th days of differentiation, respectively (Fig.…”