Xiaonan Zhang,Kang Chen,Bo Wei,Xingwang Liu,Zeming Lei,Xizhuang Bai
Glucocorticoid-induced osteoporosis (GIOP) is the primary cause of secondary osteoporosis and the existing therapeutic strategies are limited. The aim of this study is to evaluate the effects of ginsenosides (GS) Rg3 on dexamethasone (DEX)-induced osteoporosis in vivo and in vitro. GIOP rat was established by DEX injection for 5 weeks and treated by GS Rg3 10 or 20 mg/kg. Body weight and bone mineral density (BMD) of rats were measured at the beginning and the end of the experiment. Histological changes of femurs were observed using HE staining. The in vitro model was established on primary osteoblasts induced by DEX. CCK-8 assay was used to test the cell viability. Bone metabolism markers in serum or primary osteoblasts were detected using biochemical kits. Real time PCR and western blot were used to measure nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG), bone morphogenic protein-2 (BMP-2), BMP receptor 1A (BMPR1A) and Runx2 expression. The results demonstrated that GS Rg3 prevented DEX-induced body weight and BMD reduction, enhanced secretion of bone formation markers and decreased bone resorption markers. In addition, GS Rg3 was found to prevent the suppression of BMP-2/BMPR1A/Runx2 signals induced by DEX both in GIOP rats and primary osteoblasts. Inhibition of BMP-2 by noggin completely blocked the bone-alkaline phosphatase-secretion-promoted effect of GS Rg3 in vitro. These data suggest that GS Rg3 attenuates GIOP through regulating BMP-2 signaling pathway. This study provides a potential drug candidate for GIOP therapy.
Lei Fan,Qi Tang,Yutong Wang,Hang Sun,Ge Li,Yi Yang,Huiying Zhu,Zhaoyuan Liu,He Wang,Hongyan Wang,Qing Jing,Christopher L. Antos,Hui Xiao,Renchu Guan,Gang Pei,Florent Ginhoux,Zhigang Zhou,An Zeng
Adult hearts scar after injury, while neonatal hearts regenerate. The mechanisms underlying this dichotomy remain unclear. Through comparative spatiotemporal single-cell analyses and dual recombinase-mediated lineage tracing, we uncovered an injury-induced Clusterin + cardiomyocyte ( Clu + CM) population that coordinates reparative, anti-inflammatory macrophage activity. Following injury, Clu + CMs emerge in the border zone of regenerative hearts but are scarce in non-regenerative contexts. These CMs secrete CLU, which binds to macrophage Toll-like receptor 4 (TLR4), attenuating inflammation and promoting reparative polarization through Cpt1a -dependent fatty acid oxidation. These macrophages secrete bone morphogenetic protein 2 (BMP2), activating bone morphogenetic protein receptor, type 1A (BMPR1A) signaling in CMs to drive proliferation. Reduced CLU levels in myocardial infarction patients correlate with impaired cardiac function, whereas Clu overexpression or transplantation of engineered CLU + human cardiac organoids recapitulates this regenerative modulation, enhancing myocardial repair in adult mice. Our findings reveal a critical cardio-immune mechanism whereby Clu + CMs reprogram macrophages to resolve inflammation and stimulate CM proliferation, providing potential strategies for cardiac regeneration.
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