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Osteoporotic bones have reduced spongy bone mass, altered bone architecture, and increased marrow fat. Bone marrow stem cells from osteoporotic patients are more likely to differentiate into adipocytes than control cells, suggesting that adipocyte differentiation may play a role in osteoporosis. VEGF is highly expressed in osteoblastic precursor cells and is known to stimulate bone formation. Here we tested the hypothesis that VEGF is also an important regulator of cell fate, determining whether differentiation gives rise to osteoblasts or adipocytes. Mice with conditional VEGF deficiency in osteoblastic precursor cells exhibited an osteoporo-sis-like phenotype characterized by reduced bone mass and increased bone marrow fat. In addition, reduced VEGF expression in mesenchymal stem cells resulted in reduced osteoblast and increased adipocyte differentiation. Osteoblast differentiation was reduced when VEGF receptor 1 or 2 was knocked down but was unaf-fected by treatment with recombinant VEGF or neutralizing antibodies against VEGF. Our results suggested that VEGF controls differentiation in mesenchymal stem cells by regulating the transcription factors RUNX2 and PPARγ2 as well as through a reciprocal interaction with nuclear envelope proteins lamin A/C. Impor-tantly, our data support a model whereby VEGF regulates differentiation through an intracrine mechanism that is distinct from the role of secreted VEGF and its receptors., Introduction Osteoporosis, skeletal fragility associated with reduced quantity and quality of bone, is a major problem in the aging population. During aging, the balance between bone formation and resorption shifts [...]

Studies of proliferative hemangiomas have led to the discovery that interactions of endothelial cells with extracellular matrix and/or Vascular Endothelial Growth Factor ( VEGF)-A stimulate the expression of VEGFR1, the VEGF decoy receptor, and suppress VEGF-dependent VEGFR2 signalling by a mechanism that requires the matrix-binding receptor Anthrax Toxin Receptor ( ANTXR)1, VEGFR2, β1 integrin and the Nuclear Factor of Activated T cells (NFAT). In hemangioma endothelial cells, all these components are present, but are functionally compromised, so that the levels of VEGFR1 are extremely low and VEGFR2 signalling is constitutively active. Consequently, the levels of Hypoxia Inducible Factor ( HIF)-1α and its transcriptional targets, VEGF-A and C-X-C motif chemokine 12 (CxCl12), are elevated and a positive VEGF-A feedback loop is established. Overexpression of ANTXR1, carrying a heterozygous Ala-to-Thr mutation, induces hemangioma-like signalling in control endothelial cells; VEGF signalling is normalized when wild-type ANTXR1 is overexpressed in hemangioma cells. These findings suggest that ANTXR1 functions as a negative regulator of VEGF-A signalling. Studies of a mouse model of the Growth Retardation, Alopecia, Pseudo-anodontia and Optic Atrophy ( GAPO) syndrome, caused by the loss-of-function mutations in ANTXR1, as well as knock-in mice carrying the Ala-to-Thr ANTXR1 mutation, confirm that ANTXR1 functions as a suppressor of VEGF-A signalling. Cutaneous endothelial cells isolated from ANTXR1-deficient mice exhibit low levels of VEGFR1, elevated levels of VEGF-A, HIF-1α and CxCl12 and activated VEGFR2 signalling as in hemangioma. Increased numbers of myeloid cells in the skin of ANTXR1-deficient mice are associated with reduced vascularity and increased skin fibrosis, suggesting a mechanism for hemangioma involution and replacement by fibrotic scars. Through controlling VEGF-A signalling and extracellular matrix synthesis, ANTXR1 is emerging as a key regulator of skeletal and connective tissue development and homeostasis. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor A (Vegfa) has important roles in endochondral bone formation. Osteoblast precursors, endothelial cells and osteoclasts migrate from perichondrium into primary ossification centers of cartilage templates of future bones in response to Vegfa secreted by (pre)hypertrophic chondrocytes. Perichondrial osteolineage cells also produce Vegfa, but its function is not well understood. By deleting Vegfa in osteolineage cells in vivo, we demonstrate that progenitor-derived Vegfa is required for blood vessel recruitment in perichondrium and the differentiation of osteoblast precursors in mice. Conditional deletion of Vegfa receptors indicates that Vegfa-dependent effects on osteoblast differentiation are mediated by Vegf receptor 2 (Vegfr2). In addition, Vegfa/Vegfr2 signaling stimulates the expression and activity of Indian hedgehog, increases the expression of β-catenin and inhibits Notch2. Our findings identify Vegfa as a regulator of perichondrial vascularity and osteoblast differentiation at early stages of bone development. [ABSTRACT FROM AUTHOR]

Osteoporotic bones have reduced spongy bone mass, altered bone architecture, and increased marrow fat. Bone marrow stem cells from osteoporotic patients are more likely to differentiate into adipocytes than control cells, suggesting that adipocyte differentiation may play a role in osteoporosis. VEGF is highly expressed in osteoblastic precursor cells and is known to stimulate bone formation. Here we tested the hypothesis that VEGF is also an important regulator of cell fate, determining whether differentiation gives rise to osteoblasts or adipocytes. Mice with conditional VEGF deficiency in osteoblastic precursor cells exhibited an osteoporosis- like phenotype characterized by reduced bone mass and increased bone marrow fat. In addition, reduced VEGF expression in mesenchymal stem cells resulted in reduced osteoblast and increased adipocyte differentiation. Osteoblast differentiation was reduced when VEGF receptor 1 or 2 was knocked down but was unaffected by treatment with recombinant VEGF or neutralizing antibodies against VEGF. Our results suggested that VEGF controls differentiation in mesenchymal stem cells by regulating the transcription factors RUNX2 and PPARγ2 as well as through a reciprocal interaction with nuclear envelope proteins lamin A/C. Importantly, our data support a model whereby VEGF regulates differentiation through an intracrine mechanism that is distinct from the role of secreted VEGF and its receptors. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor A (VEGF), a key factor in angiogenesis, plays an essential role in skeletal development and postnatal homeostasis. VEGF serves as a survival factor for chondrocytes and couples the resorption of cartilage with bone formation during endochondral ossification. Recently, it has also been found to regulate the balance between osteoblast and adipocyte differentiation in bone marrow mesenchymal stem cells. Surprisingly, this regulatory function of VEGF is not based on paracrine signaling involving cell surface receptor activation. Instead, the mechanism appears to utilize intracellular VEGF, which is functionally linked to the nuclear envelope protein lamin A. Lamin A and VEGF control osteoblast and adipocyte differentiation by regulating the levels of the osteoblast and adipocyte transcription factors Runx2 and PPARγ, respectively. These data raise the intriguing possibility that loss of bone mass during aging may be manipulated by controlling the levels and activity of intracellular VEGF in bone marrow mesenchymal stem cells.

Collagen gels are promising scaffolds to prepare an implant for cartilage repair but several parameters, such as collagen concentration and composition as well as cell density, should be carefully considered, as they are reported to affect phenotypic aspects of chondrocytes. In this study we investigated whether the presence of collagen type I or II in gel lattices affects matrix contraction and relative gene expression levels of matrix proteins, MMPs and the subsequent degradation of collagen by goat articular chondrocytes. Only floating collagen I gels, and not those attached or composed of type II collagen, contracted during a culture period of 12 days. This coincided with an upregulation of both Mmp13 and -14 gene expression, whereas Mmp1 expression was not affected. The release of hydroxyproline in the culture medium, indicating matrix degradation, was increased five-fold in contracted collagen I gels compared to collagen II gels without contraction. Furthermore, blocking contraction of collagen I gels by cytochalasin B inhibited Mmp13 and -14 expression and the release of hydroxyproline. The expression of cartilage-specific ECM genes was decreased in contracted collagen I gels, with increased numbers of cells with an elongated morphology, suggesting that matrix contraction induces dedifferentiation of chondrocytes into fibroblast-like cells. We conclude that the collagen composition of the gels affects matrix contraction by articular chondrocytes and that matrix contraction induces an increased Mmp13 and -14 expression as well as matrix degradation., (Copyright © 2011 John Wiley & Sons, Ltd.)