Abstract
In the field of bone research, various natural derivatives have emerged as candidates for osteoporosis treatment by targeting abnormally elevated osteoclastic activity. Methyl gallate, a plant-derived phenolic compound, is known to have numerous pharmacological effects against inflammation, oxidation, and cancer. Our purpose was to explore the relation between methyl gallate and bone metabolism. Herein, we performed screening using methyl gallate by tartrate resistant acid phosphatase (TRAP) staining and revealed intracellular mechanisms responsible for methyl gallate-mediated regulation of osteoclastogenesis by Western blotting and quantitative reverse transcription polymerase chain reaction (RT-PCR). Furthermore, we assessed the effects of methyl gallate on the characteristics of mature osteoclasts. We found that methyl gallate significantly suppressed osteoclast formation through Akt and Btk-PLCγ2-Ca2+ signaling. The blockade of these pathways was confirmed through transduction of cells with a CA-Akt retrovirus and evaluation of Ca2+ influx intensity (staining with Fluo-3/AM). Indeed, methyl gallate downregulated the formation of actin ring-positive osteoclasts and resorption pit areas. In agreement with in vitro results, we found that administration of methyl gallate restored osteoporotic phenotype stimulated by acute systemic injection of lipopolysaccharide in vivo according to micro-computed tomography and histological analysis. Our data strongly indicate that methyl gallate may be useful for the development of a plant-based antiosteoporotic agent.
Highlights
The development of rigidity and healthy conditions in the skeletal system are mainly influenced by a continuous and complex process, bone remodeling, which is dependent on systemic energy metabolism [1]
To examine the effect of methyl gallate on RANK ligand (RANKL)-induced osteoclast differentiation, various concentrations (0, 1, 5, and 10 μM) of methyl gallate were incubated with bone marrow macrophages (BMMs) in the presence of macrophage colony-stimulating factor (M-CSF) (30 ng/mL) and RANKL (100 ng/mL)
The number of tartrate resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) was significantly decreased in BMM cultures treated with methyl gallate at the concentrations of 5 and 10 μM (Figure 1B)
Summary
The development of rigidity and healthy conditions in the skeletal system are mainly influenced by a continuous and complex process, bone remodeling, which is dependent on systemic energy metabolism [1]. The activation phase is regulated by the effects of local transforming growth factor beta (TGF-β1) on mesenchymal stem cells of the osteoblast lineage. These cells interact with hematopoietic precursor cells to generate osteoclasts in the resorption phase. Functional osteoblasts lie at the surface of the existing matrix and accumulate fresh layers of bone in the formation phase. This tight orchestration of each phase essentially requires the balance between osteoclast-mediated bone-resorptive activity and osteoblast-mediated bone formative activity [2,3,4]
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