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The mechanism of metformin combined with total flavonoids of Rhizoma Drynariae on ovariectomy-induced osteoporotic rats

Ningning Jiang,Hui Jin,Kun Yang,Zhongyuan Zhang,Wenshu Xu,Xiaoxue Chen,Zhenhua Zhang,Hui Xu

The present study evaluated the in vitro effect of metformin (Met) and total flavonoids of Rhizoma Drynariae (TFRD) on osteoclasts, osteocytes, and osteoblasts at different stages. We also assessed the effect and mechanism of treatment with Met combined with TFRD on ovariectomy (OVX)-induced osteoporosis in rats. The results showed that Met combined with TFRD significantly promoted the migration of osteoprogenitor cells and stimulated the differentiation and maturation of osteoblast precursor cells. Furthermore, Met combined with TFRD treatment significantly inhibited the osteogenic inhibitor sclerostin (SOST)/dickkopf 1 (DKK1) protein expression and the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio in osteocytes. In the in vivo study, Met combined with TFRD effectively reduced bone resorption markers levels, including type-I collagen carboxy-terminal peptide (CTX-1) and tartrate-resistant acid phosphatase (TRAP), and remarkably increased the bone formation marker propeptide of type I procollagen (PINP) level in the serum of rats with osteoporosis. Met combined with TFRD treatment improved bone mineral density (BMD), trabecular microstructure, and mechanical properties of osteoporotic rats. Mechanistically, Met combined with TFRD downregulated SOST and DKK1 levels, and upregulated Wnt10b, β-catenin, runt-related transcription factor 2 (Runx2) et al. Meanwhile, Met combined with TFRD treatment reduced the RANKL/OPG ratio, and reduced the receptor activator of nuclear factor-κB (RANK), nuclear factor of activated T cells c1 (NFATC1), and TRAP levels. In conclusion, Met combined with TFRD ameliorated bone mass in osteoporotic rats through regulating Wnt/β-catenin signaling pathway and OPG/RANKL/RANK axis.