Norisoboldine, a Natural Alkaloid from Lindera aggregata (Sims) Kosterm, Promotes Osteogenic Differentiation via S6K1 Signaling Pathway and Prevents Bone Loss in OVX Mice.

Abstract

Norisoboldine (NOR) is a major isoquinoline alkaloid component in the traditional Chinese herbal plant Lindera aggregata (Sims) Kosterm, with previously reported anti-osteoclast differentiation and antiarthritis properties. However, the roles of NOR on osteoblasts, bone marrow mesenchymal stem cells (BMSCs), and osteoporosis in vivo have never been well established. This study investigates the ability of NOR to improve bone formation in vitro and in vivo. Osteoblasts and BMSCs are used to study the effect of NOR on osteogenic and adipogenic differentiation. It finds that NOR promotes osteogenic differentiation of osteoblasts and BMSCs, while inhibiting adipogenic differentiation of BMSCs by reducing the relative expression of peroxisome proliferator-activated receptorγ (Ppar-γ) and adiponectin, C1Q and collagen domain containing (Adipoq). Mechanistic studies show that NOR increases osteoblast differentiation through the mechanistic target of rapamycin kinase (mTOR)/ribosomal protein S6 kinase; polypeptide 1 (S6K1) pathway, and treatment with an mTOR inhibitor rapamycin blocked the NOR-induced increase in mineral accumulation. Finally, the study evaluates the therapeutic potential of NOR in a mouse model of ovariectomy (OVX)-induced bone loss. NOR prevents bone loss in both trabecular and cortical bone by increasing osteoblast number and phospho-S6K1 (p-S6K1) expression in osteoblasts. NOR effects in enhancing osteoblast-induced bone formation via S6K1 pathway, suggesting the potential of NOR in osteoporosis treatment by increasing bone formation.