(P04-038-24) Narirutin Improves Cisplatin-Induced Osteosarcopenia and Osteoblastogenesis via Wnt/β-catenin and MAPK Signaling Pathways by Activating Irisin

Objectives: Osteosarcopenia is a new syndrome characterized by the presence of both osteopenia/osteoporosis and sarcopenia, resulting in poor survival and prognosis in cancer patients receiving chemotherapy. Given bones and muscles communicate extensively by secreting biochemical signals such as osteokines and myokines, bone-muscle crosstalk has emerged as a novel therapeutic approach for osteosarcopenia. Here, we investigated the effects of narirutin (NR), a dietary flavonoid in citrus fruits, on cisplatin-induced osteosarcopenia and the relevant mechanisms involved in bone-muscle crosstalk.

Methods: Seven-week-old male C57BL/6 mice were randomized into normal control, Lewis lung cancer model (LLC), LLC + cisplatin, or LLC + cisplatin + NR groups. After 3 weeks, muscle weight was measured and femurs were analyzed by microCT and H&E staining. MC3T3-E1 murine pre-osteoblast cells were differentiated with conditioned media of C2C12 myotubes cultured with 50 μM cisplatin and/or 1 μM NR for 24 hours, and further analyzed for the expression of osteoblastic markers.

Results: NR administration ameliorated both cisplatin-induced muscle atrophy, a loss of muscle mass, and trabecular bone (Tb) volume ratio, Tb number, and Tb separation in vivo. NR induced a significant increase in the number of osteoblast (OB) and OB/trabecular area, and OB perimeter in femurs. Similarly, NR treatment significantly enhanced the expression of RUNX2, the key regulator of osteogenesis, and osteogenic markers including ALP, COL1A1, OPN, and OCN in vitro. Furthermore, the expression of irisin, a novel exercised-induced myokine positively associated with bone anabolic metabolism, was significantly increased in response to NR treatment. Consistently, NR significantly upregulated not only the expression of Wnt/β-catenin signaling pathway genes (Wnt5a, β-catenin, LRP5, and Fzd4) but MAPK signaling pathway genes (p38α, ERK1, ERK2, JNK1 and JNK2), thereby contributing to enhanced osteoblast differentiation.

Conclusions: Overall, narirutin improves cisplatin-induced osteosarcopenia and osteoblastogenesis via Wnt/β-catenin and MAPK signaling pathways by activating irisin, suggesting that narirutin could be a potential candidate for the prevention and treatment of cisplatin-induced osteosarcopenia.

Funding Sources: National Research Foundation of Korea