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Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development.

ABSTRACT: 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 ?-catenin and inhibits Notch2. Our findings identify Vegfa as a regulator of perichondrial vascularity and osteoblast differentiation at early stages of bone development.

SUBMITTER: Duan X

PROVIDER: S-EPMC4460736 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development.

Duan Xuchen X Murata Yurie Y Liu Yanqiu Y Nicolae Claudia C Olsen Bjorn R BR Berendsen Agnes D AD

Development (Cambridge, England) 20150514 11

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 ...[more]

PMID: 25977369

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Project description:The WNT/?-catenin signaling pathway is a critical regulator of chondrocyte and osteoblast differentiation during multiple phases of cartilage and bone development. Although the importance of ?-catenin signaling during the process of endochondral bone development has been previously appreciated using a variety of genetic models that manipulate ?-catenin in skeletal progenitors and osteoblasts, genetic evidence demonstrating a specific role for ?-catenin in committed growth-plate chondrocytes has been less robust. To identify the specific role of cartilage-derived ?-catenin in regulating cartilage and bone development, we studied chondrocyte-specific gain- and loss-of-function genetic mouse models using the tamoxifen-inducible Col2Cre(ERT2) transgene in combination with ?-catenin(fx(exon3)/wt) or ?-catenin(fx/fx) floxed alleles, respectively. From these genetic models and biochemical data, three significant and novel findings were uncovered. First, cartilage-specific ?-catenin signaling promotes chondrocyte maturation, possibly involving a bone morphogenic protein 2 (BMP2)-mediated mechanism. Second, cartilage-specific ?-catenin facilitates primary and secondary ossification center formation via the induction of chondrocyte hypertrophy, possibly through enhanced matrix metalloproteinase (MMP) expression at sites of cartilage degradation, and potentially by enhancing Indian hedgehog (IHH) signaling activity to recruit vascular tissues. Finally, cartilage-specific ?-catenin signaling promotes perichondrial bone formation possibly via a mechanism in which BMP2 and IHH paracrine signals synergize to accelerate perichondrial osteoblastic differentiation. The work presented here supports the concept that the cartilage-derived ?-catenin signal is a central mediator for major events during endochondral bone formation, including chondrocyte maturation, primary and secondary ossification center development, vascularization, and perichondrial bone formation.

Project description:Developing novel approaches to treat skeletal disorders requires an understanding of how critical molecular factors regulate osteoblast differentiation and bone remodeling. We have reported that (1) retinoic acid receptor-related orphan receptor beta (Ror?) is upregulated in bone samples isolated from aged mice and humans in vivo; (2) Ror? expression is inhibited during osteoblastic differentiation in vitro; and (3) genetic deletion of Ror? in mice results in preservation of bone mass during aging. These data establish that Ror? inhibits osteogenesis and that strict control of Ror? expression is essential for bone homeostasis. Because microRNAs (miRNAs) are known to play important roles in the regulation of gene expression in bone, we explored whether a predicted subset of nine miRNAs regulates Ror? expression during both osteoblast differentiation and aging. Mouse osteoblastic cells were differentiated in vitro and assayed for Ror? and miRNA expression. As Ror? levels declined with differentiation, the expression of many of these miRNAs, including miR-219a-5p, was increased. We further demonstrated that miR-219a-5p was decreased in bone samples from old (24-month) mice, as compared with young (6-month) mice, concomitant with increased Ror? expression. Importantly, we also found that miR-219a-5p expression was decreased in aged human bone biopsies compared with young controls, demonstrating that this phenomenon also occurs in aging bone in humans. Inhibition of miR-219a-5p in mouse calvarial osteoblasts led to increased Ror? expression and decreased alkaline phosphatase expression and activity, whereas a miR-219a-5p mimic decreased Ror? expression and increased osteogenic activity. Finally, we demonstrated that miR-219a-5p physically interacts with Ror? mRNA in osteoblasts, defining Ror? as a true molecular target of miR-219a-5p. Overall, our findings demonstrate that miR-219a-5p is involved in the regulation of Ror? in both mouse and human bone. © 2018 American Society for Bone and Mineral Research.

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Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development.

Publications

Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development.

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