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Foxf2 represses bone formation via Wnt2b/β-catenin signaling.

ABSTRACT: Differentiation of mesenchymal stem cells (MSCs) into osteoblasts is a critical process for proper skeletal development and acquisition/maintenance of bone mass. However, since this regulatory mechanism has not yet been fully elucidated, the treatment of severe osteoporosis and fractures is a challenge. Here, through a comprehensive analysis of gene expression during the differentiation of MSCs into osteoblasts, we show that the forkhead transcription factor Foxf2 is a crucial regulator of this process. Foxf2 expression transiently increased during MSC osteoblastic differentiation. Overexpression of Foxf2 in MSCs inhibited osteoblastic differentiation, and conversely, knockdown of Foxf2 expression promoted this process. Osteoprogenitor-specific Foxf2 knockout mice developed a high bone mass phenotype due to increased bone formation. RNA-seq analysis and molecular experiments revealed that Foxf2 regulation of bone formation is mediated by Wnt2b. Knockdown of Foxf2 in mouse femurs enhanced bone regeneration in vivo. FOXF2 expression was correlated with hip bone mineral density in postmenopausal women with low bone mass. Finally, inhibition of FOXF2 promoted osteoblastic differentiation of human MSCs. This study uncovers a critical role of Foxf2 in the differentiation of MSCs into osteoblasts and provides insight into the pathogenesis associated with bone-related diseases such as osteoporosis and nonunion after fracture.

SUBMITTER: Tanaka T

PROVIDER: S-EPMC9256714 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Foxf2 represses bone formation via Wnt2b/β-catenin signaling.

Tanaka Tomoyuki T Takahashi Akira A Kobayashi Yutaka Y Saito Masanori M Xiaolong Sun S Jingquan Chen C Ito Yoshiaki Y Kato Tsuyoshi T Ochi Hiroki H Sato Shingo S Yoshii Toshitaka T Okawa Atsushi A Carlsson Peter P Inose Hiroyuki H

Experimental & molecular medicine 20220606 6

Differentiation of mesenchymal stem cells (MSCs) into osteoblasts is a critical process for proper skeletal development and acquisition/maintenance of bone mass. However, since this regulatory mechanism has not yet been fully elucidated, the treatment of severe osteoporosis and fractures is a challenge. Here, through a comprehensive analysis of gene expression during the differentiation of MSCs into osteoblasts, we show that the forkhead transcription factor Foxf2 is a crucial regulator of this ...[more]

PMID: 35668101

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Project description:Recently, we reported that extract of Dalbergia sissoo made from leaves and pods have antiresorptive and bone-forming effects. The positive skeletal effect attributed because of active molecules present in the extract of Dalbergia sissoo. Caviunin 7-O-[β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside] (CAFG), a novel isoflavonoid show higher percentage present in the extract. Here, we show the osteogenic potential of CAFG as an alternative for anabolic therapy for the treatment of osteoporosis by stimulating bone morphogenetic protein 2 (BMP2) and Wnt/β-catenin mechanism. CAFG supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur and decreased bone turnover markers better than genistein. Oral administration of CAFG to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased the expression of osteogenic genes in femur and show new bone formation without uterine hyperplasia. CAFG increased mRNA expression of osteoprotegerin in bone and inhibited osteoclast activation by inhibiting the expression of skeletal osteoclastogenic genes. CAFG is also an effective accelerant for chondrogenesis and has stimulatory effect on the repair of cortical bone after drill-hole injury at the tissue, cell and gene level in mouse femur. At cellular levels, CAFG stimulated osteoblast proliferation, survival and differentiation. Signal transduction inhibitors in osteoblast demonstrated involvement of p-38 mitogen-activated protein kinase pathway stimulated by BMP2 to initiate Wnt/β-catenin signaling to reduce phosphorylation of GSK3-β and subsequent nuclear accumulation of β-catenin. Osteogenic effects were abrogated by Dkk1, Wnt-receptor blocker and FH535, inhibitor of TCF-complex by reduction in β-catenin levels. CAFG modulated MSC responsiveness to BMP2, which promoted osteoblast differentiation via Wnt/β-catenin mechanism. CAFG at 1 mg/kg(/)day dose in ovariectomy mice (human dose ∼0.081 mg/kg) led to enhanced bone formation, reduced bone resorption and bone turnover better than well-known phytoestrogen genistein. Owing to CAFG's inherent properties for bone, it could be positioned as a potential drug, food supplement, for postmenopausal osteoporosis and fracture repair.

Project description:Objective: Studies suggest that matrix Gla protein (MGP) is associated with osteoporosis. However, the precise mechanism through which MGP regulates bone metabolism is not fully understood. The purpose of this study was to clarify the role of MGP in bone metabolism. Methods: The MGP gene in MG63 cell line was knocked down using shRNA. Cell Counting Kit-8 assay was used to detect the proliferation of MG63 cells. Moreover, the differentiation and mineralization of MG63 cells were measured through alkaline phosphatase staining and Alizarin Red S staining. Western blotting and quantitative reverse transcription-polymerase chain reaction were conducted to detect the protein and mRNA levels of components of the Wnt/β-catenin signaling pathway, such as Wnt3a, β-catenin, and Runx2. Transgenic (MGP+) mice were used to detect the effects of MGP in vivo. Results: The Cell Counting Kit-8 assay suggested that upregulated MGP could promote the proliferation of MG63 cells, whereas its downregulation inhibited proliferation. The alkaline phosphatase assay and Alizarin Red S staining showed that overexpressed MGP led to prominently upregulated differentiation and mineralization of MG63 cells. Conversely, knockdown of MGP decreased the levels of differentiation and mineralization. Western blotting and quantitative reverse transcription-polymerase chain reaction showed that overexpression of MGP upregulated Wnt3a, β-catenin, and Runx2. In contrast, knocking down MGP reduced their transcriptional levels. In vivo, overexpression of MGP inhibited the decrease in bone mineral density induced via ovariectomy in the femur, and significantly prevented bone volume fraction, trabecular number, BV/TV, and TbTh to decrease. In addition, it increased the levels of estradiol in sera. Conclusion: The findings of this study suggest that the promotion of osteoblast proliferation, differentiation, and mineralization by MGP may be a mechanism to prevent osteoporosis. Furthermore, the results show that MGP promoted the osteogenic effects via the Wnt/β-catenin signaling pathway.

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Foxf2 represses bone formation via Wnt2b/β-catenin signaling.

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Foxf2 represses bone formation via Wnt2b/β-catenin signaling.

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