ZEB1 regulates bone metabolism in osteoporotic rats through inducing POLDIP2 transcription

Abstract

Background Osteoporosis (OP) is a common metabolic bone disease mainly involving bone remodeling and blood vessels. The current study aimed to explore the role of zinc finger E-box binding homeobox 1 (ZEB1) in OP. Methods First, gene expression microarrays for OP were downloaded from the Gene Expression Omnibus database and analyzed to screen for potential targets. Subsequently, a rat OP model was constructed using ovariectomy (OVX), and osteoblastic and osteoclastic differentiation and alterations in osteoporotic symptoms were observed upon intraperitoneal injection of oe-ZEB1 lentiviral vectors. DNA polymerase delta interacting protein 2 (POLDIP2) was predicted to be a downstream target of ZEB1, which was validated by ChIP-qPCR and dual-luciferase experiments. RAW264.7 cells were subjected to lentiviral vector infection of oe-ZEB1 and/or sh-POLDIP2, followed by RANKL treatment to induce osteoclast differentiation. Results ZEB1 was poorly expressed in blood samples of postmenopausal patients with OP and in bone tissues of OVX-treated rats. Overexpression of ZEB1 or POLDIP2 in OVX rats promoted osteoblastogenesis and inhibited osteoclast differentiation. In RANKL-treated RAW264.7 cells, the transcription factor ZEB1 enhanced the expression of POLDIP2, and silencing of POLDIP2 attenuated the inhibitory effect of oe-ZEB1 on the differentiation of macrophages RAW264.7 to osteoclasts. Conclusions ZEB1 promotes osteoblastogenesis and represses osteoclast differentiation, ultimately reducing the occurrence of postmenopausal OP by elevating the expression of POLDIP2.

A Zeb1/MtCK1 metabolic axis controls osteoclast activation and skeletal remodeling

“…While Zeb1 has been reported to affect glucose and fatty acid metabolism in normal and neoplastic epithelial cells (Masin et al , 2014 ; Mathow et al , 2015 ; Zhang et al , 2016 ; Xu et al , 2018 ), our studies suggest that MtCK1 and mitochondrial activity could be critical targets in a variety of cell populations. Interestingly, a recent study described the ability of Zeb1 to regulate rat osteoclast activity by targeting the DNA polymerase interacting protein, PLODIP2, and of direct relevance to our own findings, that decreased levels of Zeb1 can be found in mononuclear cells recovered from osteoporotic women (Zhu et al , 2022 ). However, distinguishing our work from theirs, PLODIP2 expression was unaffected in our RNA‐seq data of wild‐type vs Zeb1 knockout osteoclast's.…”

Homeostatic Regulation of Pro-Angiogenic and Anti-Angiogenic Proteins via Hedgehog, Notch Grid, and Ephrin Signaling in Tibial Dyschondroplasia

“…It plays a crucial role in the transportation of growth factors to enable cell survival, interaction, and angiogenesis in different tissue regeneration vessels in the bone marrow beside the growth plate. It also exemplifies the central element of a metabolically unique bone microenvironment with advantageous access to nutrients and oxygen by improving the growth potential of adjacent perivascular cells, for example, pre-osteoprogenitors, osteoprogenitors, and mature and hypertrophic chondrocytes [3,4]. Both organ growth and tissue healing depend on forming a functional circulatory system.…”