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Osteosarcoma, considered as the primary cause of malignant bone tumors in children, necessitates novel therapeutic strategies to enhance overall survival rates. KAT7, a histone acetyltransferase, exerts pivotal functions in gene transcription and immune modulation. In light of this, our study identified a significant upregulation of KAT7 in the mRNA and protein levels in human osteosarcoma, boosting cell proliferation in vivo and in vitro. In addition, KAT7-mediated H3K14ac activation induced MMP14 transcription, leading to increased expression and facilitation of osteosarcoma cell metastasis. Subsequent bioinformatics analyses highlighted a correlation between KAT7 and adaptive immune responses, indicating CCL3 as a downstream target of KAT7. Mechanistically, STAT1 was found to transcriptionally upregulate CCL3 expression. Furthermore, overexpression of KAT7 suppressed CCL3 secretions, whereas knockdown of KAT7 enhanced its release. Overall, these findings underscore the oncogenic role of KAT7 in regulating immune responses for osteosarcoma treatment. • KAT7 was abundantly expressed in osteosarcoma. • KAT7 overexpression enhanced the expression of MMP14 by H3K14ac modification. • KAT7 inhibited the expression of CCL3 via JAK1-STAT1 signaling pathways. • STAT1 transcriptionally activated CCL3, thereby modulating immune responses. • KAT7 accelerated dissemination of OS cells in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Polyphosphate (polyP) is composed of linear polymers of orthophosphate residues linked by high-energy phosphoanhydride bonds. It has been reported to improve osteoblastic differentiation, stimulate periodontal tissue regeneration, and accelerate bone repair. The aim of this study was to evaluate the effect of polyP on the expression of FGF23, a hormone secreted mostly be mature osteoblasts and osteocytes. In this study, different types of polyP were synthesized and co-cultured with osteoblast-like UMR-106 cells. Real-time PCR and western blot were used to analyze the gene and protein expression of FGF23. We found that 1mM polyP was able to increase FGF23 expression after 4h, reaching a peak after 12–24h, with expression decreasing by 48h. We also found that polyP could activate the FGFR pathway, as evidenced by increased phosphorylation of FGFR, FRS2, and Erk1/2. When FGFR signaling was inhibited by the specific inhibitor SU5402, the effect of polyP on FGF23 expression was significantly reduced. Our results indicate that polyP is able to stimulate osteoblastic FGF23 expression and that this effect is associated with activation of the FGFR pathway. These findings provide support for the clinical use of polyP by indicating a mechanism for polyP in bone regeneration. [Copyright &y& Elsevier]

Background: Segmental bone defect is still a challenge to orthopedic surgeons. Currently available therapies for segmental bone defects have some drawbacks. Tissue engineering using pluripotent stem cells is a new, promising method for bone repair. The present study aims to promote the effect of bone defect repair using the tissue engineered bone in combination with vascularized periosteal flaps. Methods: The adenoviral vector carrying Cbfa1 transduced rabbit adipose-derived mesenchymal stem cells and gene modified tissue engineering bone (GMB) were constructed. Rabbits with radial defects were implanted with the GMB together with vascularized periosteum (group A); or GMB with free periosteum (group B); or GMB (group C), and scaffold (group D). The bone repair effect was evaluated at 4, 8, or 12 wk, respectively, after the operations. Results: Cbfa1 proteins were strongly expressed in adipose stem cells (ADSCs) that formed a stratified network on the inner surface of the polylactic acid/ polycaprolacton (PLA/PCL) pores. Bone repair was well achieved in the rabbits treated with the Cbfa1-expressing ADSCs and vascularized flap that was markedly better than those treated with either Cbfa1-expressing ADSCs alone or with vascularized flap alone. Conclusions: Combination with implanting the Cbfa1 gene-modified tissue-engineered bone and vascularized periosteum can better repair the segmental bone defects by stimulating osteogenesis, osteoinduction, and osteoconduction than using either one of the approaches. [Copyright &y& Elsevier]