TGF-β2-induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone

Abstract

Although emerging studies have implicated that Aiopoietin-like 4 Protein (ANGPTL4) is related to the aggressiveness and metastasis of many tumors, the role of ANGPLT4 in giant cell tumor (GCT) of bone was rarely investigated. The mechanism of ANGPLT4 in tumor-induced osteoclastogenesis still remains unclear. In this study, we first demonstrated that ANGPTL4 was highly expressed in GCT compared to normal tissues, while we showed that TGF-β2 released by osteoclasts induced bone resorption could increase the expression of ANGPTL4 in GCTSCs. By using the luciferase reporter assay, we found that two downstreams of TGF-β2, Smad3 and Smad4, could directly activate the promoter of ANGPTL4, which might explain the mechanism of TGF-β2-induced ANGPLT4 expression. Moreover, knockout of ANGPTL4 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT in vitro. By using the chick chorio-allantoic membrane (CAM) models, we further showed that inhibition of ANGPTL4 suppressed tumor growth and giant cell formation in vivo. In addition, some new pathways involved in ANGPTL4 application were identified through microarray assay, which may partly explain the mechanism of ANGPTL4 in GCT. Taken together, our study for the first time identified the role of ANGPLT4 in GCT of bone, which may provide a new target for the diagnosis and treatment of GCT.

Stromal Cell-Derived CCL20 Promotes Tumor Progression and Osteolysis in Giant Cell Tumor of Bone

“…Our previous studies and the literature have shown that the NF-κB signaling pathway, which plays an important role in tumor progression and osteoclast differentiation, is overactive in GCTB [3,8,34]. In addition, CCL20 is reported to promote the phosphorylation of AKT [35].…”

“…GCTSCs and BMSCs were isolated from GCTB samples and bone marrow from normal donors as previously described [3,6]. RAW 264.7 cells were obtained from the Type Culture Collection of the Chinese Academy of Sciences.…”

“…GCTSCs are currently accepted as the tumor component of GCTB and can recruit mononuclear cells to form giant cells. These giant cells can further absorb bone matrix and lead to bone breakdown [3,6,7]. RANKL/RANK are widely accepted to be key regulators of bone physiology that control osteoclast development.…”

“…GCTB predominantly occurs in the metaphysis, thoracic vertebra, and sacrum of individuals in their third and fourth decades of life and shows a female predilection [1,[3][4][5]. This kind of tumor is osteolytic and comprises three major cell populations: osteoclast-like multinuclear giant cells, mononuclear precursors of osteoclasts, and spindle-shaped stromal cells (GCTSCs) [6][7][8].…”

Angiopoietin‐like 4 production upon treatment with hypoxia and L‐mimosine in periodontal fibroblasts

“…It mediates the enhanced resorption activity of osteoclasts under hypoxic conditions . Interestingly, it is also elevated in degenerative diseases such as rheumatoid arthritis and osteonecrosis of the femoral head as well as in osteolytic tumors . The fact that pro‐inflammatory factors can induce the expression of angiopoietin‐like 4 and that angiopoietin‐like 4 itself can mediate inflammatory disease suggests that it might also play a role in periodontal disease .…”