Abstract
Osteoporosis is a common health problem worldwide caused by an imbalance of bone formation vs. bone resorption. However, current therapeutic approaches aimed at enhancing bone formation or suppressing bone resorption still have some limitations. In this study, we demonstrated for the first time that cepharanthine (CEP, derived from Stephania cepharantha Hayata) exerted a protective effect on estrogen deficiency-induced bone loss. This protective effect was confirmed to be achieved through inhibition of bone resorption in vivo, rather than through enhancement of bone formation in vivo. Furthermore, the in vitro study revealed that CEP attenuated receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast formation, and suppressed bone resorption by impairing the c-Jun N-terminal kinase (JNK) and phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathways. The inhibitory effect of CEP could be partly reversed by treatment with anisomycin (a JNK and p38 agonist) and/or SC79 (an AKT agonist) in vitro. Our results thus indicated that CEP could prevent estrogen deficiency-induced bone loss by inhibiting osteoclastogenesis. Hence, CEP might be a novel therapeutic agent for anti-osteoporosis therapy.
Highlights
Constant bone remodeling involves a fine balance between osteoclast-mediated bone resorption vs. new bone formation by osteoblasts (Kawai et al, 2011)
The various anti-osteoporotic drug approved by the US Food and Drug Administration (FDA) includes anabolic drugs and anti-resorptive drugs, such as bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin, parathyroid hormone [1–34] (Teriparatide, PTH[1–34]), and monoclonal antibodies against the receptor activator of nuclear factor κB ligand (RANKL) (Saito et al, 2017)
Bone mineral density (BMD) and bone volume/total volume (BV/TV) were slightly reversed in mice with low dose CEP treatment (5 mg/kg), there were observed to be no significant differences upon analysis (Figures 1B,C)
Summary
Constant bone remodeling involves a fine balance between osteoclast-mediated bone resorption vs. new bone formation by osteoblasts (Kawai et al, 2011). Osteoporosis, which is caused by an imbalance of osteoblasts and osteoclasts, is a common disease worldwide with high morbidity, among postmenopausal women and old people, and is characterized by decreased bone mass, abnormal bone architecture, and an increased risk of fragility fracture (Ivaska et al, 2010). One of the major concerns of current anti-resorptive drugs are that these drugs reduce bone resorption efficiently, and profoundly suppress bone formation, resulting in deceased bone remodeling and increased clinical complications, such as osteonecrosis of the jaw and other atypical fractures (Khan et al, 2009; Koh et al, 2010; Lotinun et al, 2013). Teriparatide is an anabolic drug which enhances bone formation to a greater extent than bone resorption. It is imperative to find a cost-effective drug which can inhibit bone resorption effectively, whilst maintaining or even enhancing bone formation for the treatment of osteoporosis
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