Conditional ablation of Pten in osteoprogenitors stimulates FGF signaling

Abstract

SUMMARYPhosphatase and tensin homolog deleted on chromosome ten (PTEN) is a direct antagonist of phosphatidylinositol 3 kinase. Pten is a well recognized tumor suppressor and is one of the most commonly mutated genes in human malignancies. More recent studies of development and stem cell behavior have shown that PTEN regulates the growth and differentiation of progenitor cells. Significantly, PTEN is found in osteoprogenitor cells that give rise to bone-forming osteoblasts; however, the role of PTEN in bone development is incompletely understood. To define how PTEN functions in osteoprogenitors during bone development, we conditionally deleted Pten in mice using the cre-deleter strain Dermo1cre, which targets undifferentiated mesenchyme destined to form bone. Deletion of Pten in osteoprogenitor cells led to increased numbers of osteoblasts and expanded bone matrix. Significantly, osteoblast development and synthesis of osteoid in the nascent bone collar was uncoupled from the usual tight linkage to chondrocyte differentiation in the epiphyseal growth plate. The expansion of osteoblasts and osteoprogenitors was found to be due to augmented FGF signaling as evidenced by (1) increased expression of FGF18, a potent osteoblast mitogen, and (2) decreased expression of SPRY2, a repressor of FGF signaling. The differentiation of osteoblasts was autonomous from the growth plate chondrocytes and was correlated with an increase in the protein levels of GLI2, a transcription factor that is a major mediator of hedgehog signaling. We provide evidence that increased GLI2 activity is also a consequence of increased FGF signaling through downstream events requiring mitogen-activated protein kinases. To test whether FGF signaling is required for the effects of Pten deletion, we deleted one allele of fibroblast growth factor receptor 2 (FGFR2). Significantly, deletion of FGFR2 caused a partial rescue of the Pten-null phenotype. This study identifies activated FGF signaling as the major mediator of Pten deletion in osteoprogenitors.

Deletion of the PH-domain and Leucine-rich Repeat Protein Phosphatase 1 (Phlpp1) Increases Fibroblast Growth Factor (Fgf) 18 Expression and Promotes Chondrocyte Proliferation

“…Conditional deletion of PTEN, a phosphatase that suppresses PI3K/ Akt signaling upstream of Phlpp1, in limb progenitor cells enhanced Fgf18 expression (36). The authors attributed this regulation to decreased levels of FoxO1, which represses Fgf18 promoter activity (36). We also found that disrupting the substrate binding ability of Phlpp1 enhances Fgf18 expression, and that this effect is antagonized by expression of an Akt-insensitive FoxO1 mutant.…”

“…FoxO1 Represses Fgf18 Expression in Chondrocytes-FoxO1 represses Fgf18 transcription (36) and therefore may link enhanced Akt2 signaling to Erk1/2 activation in Phlpp1 Ϫ/Ϫ chondrocytes. To test this hypothesis, a Phlpp1 deletion mutant (Phlpp1⌬C) that inhibits interactions between Akt2 and Phlpp1 was introduced in chondrogenic ATDC5 cells (18).…”

“…Conditional deletion of PTEN, a phosphatase that suppresses PI3K/ Akt signaling upstream of Phlpp1, in limb progenitor cells enhanced Fgf18 expression (36). The authors attributed this regulation to decreased levels of FoxO1, which represses Fgf18 promoter activity (36).…”

MicroRNA‐106b in cancer‐associated fibroblasts from gastric cancer promotes cell migration and invasion by targeting PTEN

“…PTEN can modulate glioma response to the inhibition of HGF/c-Met signaling pathway [45], and PTEN loss amplifies c-Met-induced glioblastoma malignancy [46]. In addition, PTEN loss also induces autocrine FGF signaling to promote skin tumorigenesis [47], and lack of PTEN in osteoprogenitor cells resulted in increased osteoblast numbers and expanded bone matrix by stimulating FGF signaling [48]. Thus, in our study, up-regulation of PTEN expression in CAFs inhibited gastric cancer cell migration and invasion, which is probably mediated through regulating the expression and secretion of these growth factors and chemokines.…”

MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation

“…We used miRanda (19), PicTar (20), and TargetScan (21) to predict the targets of miR-188. Among the predicted genes, we chose 6 for further analysis-histone deacetylase 9 (Hdac9), RPTORindependent companion of MTOR complex 2 (Rictor), phosphatase and tensin homolog (Pten), zinc finger protein 281 (Znf281), GLIS family zinc finger 3 (Glis3), and ephrin B2 (Efnb2)-which had been reported to participate in bone metabolism (22)(23)(24)(25)(26)(27)(28). Overexpression or inhibition of miR-188 changed endogenous levels of HDAC9 and RICTOR protein, but not the others ( Figure 8A).…”