Abstract
Osteoporosis, a metabolic bone disease, is characterized by an excessive formation and activation of osteoclasts. Anti-catabolic treatment using natural compounds has been proposed as a potential therapeutic strategy against the osteoclast related osteolytic diseases. In this study, the activity of berberine sulfate (an orally available form of berberine) on osteoclast differentiation and its underlying molecular mechanisms of action were investigated. Using bone marrow macrophages (BMMs) derived osteoclast culture system, we showed that berberine sulfate at the dose of 0.25, 0.5 and 1 μM significantly inhibited the formation of osteoclasts. Notably, berberine sulfate at these doses did not affect the BMM viability. In addition, we observed that berberine sulfate inhibited the expression of osteoclast marker genes, including cathepsin K (Ctsk), nuclear factor of activated T cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAcP, Acp5) and Vacuolar-type H+-ATPase V0 subunit D2 (V-ATPase d2). Luciferase reporter gene assay and Western blot analysis further revealed that berberine sulfate inhibits receptor for activation of nuclear factor ligand (RANKL)-induced NF-κB and NFAT activity. Taken together, our results suggest that berberine sulfate is a natural compound potentially useful for the treatment of osteoporosis.
Highlights
Bone remodelling is a continuous and dynamic process regulated by osteoclastic bone resorption and osteoblastic bone formation [1]
Our results showed that the number of osteoclasts was significantly reduced in a dose-dependent manner, with an IC50 of 0.25 μM (Figure 1B–D)
Through screening of natural compounds that exhibit inhibitory effects on osteoclastogenesis and RANKL signalling, we found that berberine sulfate is capable of inhibiting osteoclast formation, osteoclast marker genes expression, and RANKL-induced nuclear factor κB (NF-κB) and NFAT activities, suggesting that berberine sulfate is a potential anti-catabolic agent for the treatment of osteoporosis
Summary
Bone remodelling is a continuous and dynamic process regulated by osteoclastic bone resorption and osteoblastic bone formation [1]. Overproduction and/or excessive activation of osteoclasts can lead to osteolytic bone diseases, such as postmenopausal osteoporosis and Paget’s disease of the bones [2]. Osteoclasts are multinuclear giant cells derived from the monocyte/macrophage lineage of hematopoietic stem cells. There are two key osteoclastogenic cytokines: macrophage colony-stimulating factor (M-CSF) and receptor for activation of nuclear factor κB (NF-κB) (RANK) ligand (RANKL). M-CSF causes the proliferation of early macrophage/osteoclast precursors, while RANKL acting via its receptor RANK on these precursors causes them to differentiate into mature osteoclasts. Recent studies have identified NFATc1 as a key RANKL-mediated transcription factor. NFATc1 is capable of inducing transcription of diverse osteoclast-associated genes, such as those coding for tartrate-resistant acid phosphatase (TRAcP, Acp5), cathepsin K (Ctsk), and calcitonin receptor [4]. Inhibition of RANKL-mediated signalling molecules may contribute to the treatment and prevention of osteolytic bone diseases
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