Osteoblast-specific expression of MEF induces osteopenia through downregulation of osteoblastogenesis and upregulation of osteoclastogenesis

Abstract

In bone remodeling, various transcriptional factors are involved, and the deficiency or overexpression of some of these factors results in bone defects. Myeloid elf-1-like factor (MEF) is one of the Ets transcription factors that control the expression of genes that are critical for biologic processes such as cell proliferation, differentiation, and death. Previously, we reported that MEF promotes cell proliferation and functions as a negative regulator of osteogenic differentiation by interacting directly with Runx2 and suppressing its transcriptional activity. To investigate the in vivo function of MEF in bone formation and bone remodeling in vivo, we generated transgenic mice that overexpress MEF in osteoblasts under the control of the 2.3-kb Col1a1 promoter, named Col1a1-MEF. Femoral bone in Col1a1-MEF transgenic mice exhibited low bone mass with fewer trabecular bones and thinner and less developed cortical bones. The mineralized volume fraction (BV/TV) and bone-forming rate (BFR) were remarkably decreased to about 63% and 40%, respectively, in 6-week-old MEF transgenic mice compared with wild-type mice. In addition, reduced bone mineral density was observed in lumbar vertebrae of Col1a1-MEF transgenic mice. The number of TRACP þ osteoclasts was increased in Col1a1-MEF transgenic mice and MEF-overexpressing MC3T3-E1 cells. All these in vivo results suggest that MEF suppresses bone formation by osteoblasts and facilitates bone resorption by activating osteoclasts indirectly. ß

Chitosan nanofiber scaffold improves bone healing via stimulating trabecular bone production due to upregulation of the Runx2/osteocalcin/alkaline phosphatase signaling pathway

“…34 After implanting the chitosan nanofiber scaffolds into the bone defect sites for 21 days, the animals were sacrificed, and the femurs were collected. After removing the muscle and connective tissues, the femurs were weighed and photographed.…”

PTH regulates myleoid ELF-1-like factor (MEF)-induced MAB-21-like-1 (MAB21L1) expression through the JNK1 pathway

“…Thus, we focused on the regulatory mechanisms of MEF on MAB21L1 transcription in osteoblast cells. Because MEF appeared to be a negative regulator of osteoblast differentiation in our previous studies [Kim et al, 2007; Seul et al, 2011], we speculated that MAB21L1 , which is up‐regulated by MEF, could also be involved in suppressing several catabolic osteogenic factors in the osteoblast differentiation process.…”

“…Over‐expression of MEF suppresses the expression of osteogenic related genes, such as ALP, Dlx5, OP, and OC, which are required for the terminal differentiation of an osteoblast. Moreover, osteoblast‐specific expression of MEF induced osteopenia through down‐regulation of osteoblastogenesis and up‐regulation of osteoclastogenesis [Seul et al, 2011]. Furthermore, our unpublished data also showed that overexpression of MEF or Mab21 could induce apoptosis of MG63 osteoblastic cells by increasing the level of cleaved caspase‐3.…”

“…In our previous study, we showed that the expression of MEF suppressed BMP2 action, which up‐regulated Runx2 activity and the expression of its target genes in preosteoblast MC3T3E1 cells [Kim et al, 2007]. Our recent study also demonstrated that osteoblast‐specific expression of MEF induces osteopenia by down‐regulating osteogenesis and up‐regulating osteoclastogenesis in transgenic mice [Seul et al, 2011]. Conversely, MEF is down‐regulated during BMP2‐induced osteoblast differentiation.…”

ELF4 (E74-like factor 4 (ets domain transcription factor))

“…ELF4 also regulates self-renewal of braintumor stem cells (Bazzoli et al, 2012). In addition, ELF4 plays an important role in osteogenic differentiation and bone development (Kim et al, 2007;Seul et al, 2011;Baek et al, 2012). It mediates DNA damage response (Morales et al, 2008;Sashida et al, 2011).…”