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A bone regenerative strategy based on extracellular vesicles transporting citrate for promoting biomineralization [timepoint]

ABSTRACT: The mineralization of extracellular matrix (ECM) rich in collagen is a biological process in many bones. It is well known that organic molecules from the extracellular matrix of mineralized tissues are crucial for constructing apatite minerals. Here we found that differences in cellular metabolic status significantly affect the degree of mineralization. The metabolite citrate, as a component of apatite nanocomposites, is crucial to the biomineralization of bones. Citrate is transported to the ECM through extracellular vesicles (EVs) and amorphous calcium phosphate (ACPs). Functionally, citrate can bridge more Ca2+ in EVs, contributing to higher intra-fiber mineralization. EVs produced by cells with active metabolic levels can improve the mineralization of poorly mineralized cells. The results indicate that the content of EVs can reflect the metabolic state of cells, thereby regulating the function of ECM. In general, this work reveals the complex metabolic process as a way to regulate biomineralization and proposes a new form of molecular transport, which provides a new bio-inspired strategy for bone regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE240536 | GEO | 2025/10/01

REPOSITORIES: GEO

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Project description:We used gene array analysis of cortical bone to identify Phex-dependent gene transcripts regulating Fgf23 production and mineralization in Hyp mice. We discovered that activation of Fgf receptor- and Wnt-pathways contribute to increased Ffg23 gene transcription in Hyp bone. We found evidence in Hyp bone for increased expression of Fgf1, Fgf7, and Egr2 in the Fgf-signaling pathway and decrements in Sost and Cpz and increments in Sfrp1 and 4 in the Wnt-signaling pathway. Moreover, activation of Fgf and Wnt-signaling stimulated, whereas Tgf β inhibited Fgf23 promoter activity in osteoblasts. We also observed reductions in Bmp1, a metalloproteinase that metabolizes the Fgf23 regulatory extracellular matrix protein Dmp1. These findings suggest that elevation of Fgf23 expression in osteocytes is regulated by interactions between cell surface expression of Phex, extracellular matrix proteins and paracrine effects of Fgf and Wnt. Alterations were also found in enzymes regulating the posttranslational processing and stability of Fgf23, including decrements in the glycosyltransferase Galnt3 and the proprotein convertase Pcsk5. In addition, we found that the Pcsk5 and the glycosyltransferase Galnt3 were decreased in Hyp bone, suggesting that reduced post-translational processing of FGF23 may also contribute to increased Fgf23 levels in Hyp mice. With regards to mineralization, we identified additional candidates to explain the intrinsic mineralization defect in Hyp osteoblasts, including increases in the mineralization inhibitors Mgp and Thbs4, as well as increases in local pH altering factors, carbonic anhydrase 12 (Car12) and 3 (Car3) and the sodium-dependent citrate transporter (Slc13a5). These studies demonstrate the complexity of gene expression alterations in bone that accompanies inactivating Phex mutations and identify novel pathways that may coordinate Fgf23 expression and mineralization of extracellular matrix in Hyp bone. We isolated total RNAs from long bones of both WT and Hyp mice at 12 days of age. Since the RNA yields from the long bones are very low, we combined 2 bone samples with same genotype (WT or Hyp) for one RNA extraction. We will compare the difference of the gene expressions between Hyp and WT. We will use 4 samples in each animal condition.

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A bone regenerative strategy based on extracellular vesicles transporting citrate for promoting biomineralization [timepoint]

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