Wang Chunli,Xu Mingzhi,Bai Yafei,Pan Mingjiao,Qi Yonghui,Chen Ruman
Vascular calcification (VC), a major complication in chronic kidney disease (CKD), is predominantly driven by osteoblastic differentiation. Recent studies have highlighted the crucial role of microRNAs in CKD’s pathogenesis. Here, our research focused on the effects of miR-204-5p and its molecular mechanisms within VC. We initially found a notable decrease in miR-204-5p levels in human aortic vascular smooth muscle cells stimulated with inorganic phosphate, using this as a VC model in vitro. Following the overexpression of miR-204-5p, a decrease in VC was observed, as indicated by alizarin red S staining and measurements of calcium content. This decrease was accompanied by lower levels of the osteogenic marker, runt-related transcription factor 2, and higher levels of α-smooth muscle actin, a marker of contractility. Further investigation showed that calcium/calmodulin-dependent protein kinase 1 (CAMK1), which is a predicted target of miR-204-5p, promotes VC. Conversely, overexpressing miR-204-5p reduced VC by suppressing CAMK1 activity. Overexpressing miR-204-5p also effectively mitigated aortic calcification in an in vivo rat model. In summary, our research indicated that targeting the miR-204-5p/CAMK1 pathway could be a viable strategy for mitigating VC in CKD patients.
Yizhou Zhu,Chaofeng Wang,Can Ai,Yiming Xiang,Congyang Mao,Wei Qiao,Jun Wu,John Akrofi Kubi,Xiangmei Liu,Shuilin Wu,Xin Zhao,Bin Li,Kelvin W. K. Yeung
Early osteoimmune microenvironment disorder at the interface between bone and implant can lead to implant loosening, which prolongs patient convalescence, exacerbates postoperative complications, and potentially results in implant failure. The timely regulation of macrophages primarily orchestrates the entire long-term regeneration process. Here, it is proposed to precisely direct macrophage polarization using localized photoelectrical signals generated by an excitable surface in response to remote stimulation via near-infrared light (NIR). The photocurrent generated from the n–n heterojunction between calcium titanate (CaTiO 3 ) and defective titanium dioxide (TiO 2 -V o ) on the excitable surface can accurately direct macrophage polarization, suppressing acute inflammation at the early stage of post-implantation and establishing a favorable osteoimmune microenvironment that promotes bone-to-implant integration. Mechanistic study reveals that photoelectric signals initiate increased calcium influx via voltage-gated calcium ion channels, subsequently modulating calcium/calmodulin-dependent protein kinase kinase 2 (Camkk2) and calcium/calmodulin-dependent protein kinase I (Camk1) expression to regulate macrophage polarization. This optimization of the osteoimmune microenvironment results in enhanced mesenchymal stem cells (MSCs) recruitment and osteogenesis, ultimately accelerating bone-to-implant integration within 14 days post-implantation. This research presents a novel method for adjusting in vivo spatiotemporal immune responses through the use of noninvasive and externally-controlled targeted stimulations.
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