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Attenuation of osteoclastogenesis and osteoclast function by apigenin
Sanghamitra Bandyopadhyay1, Jean-Marc Lion, Romuald Mentaverri
1Genetics and Aging Research Unit, Psychiatry Department, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Abstract:
The physiological effects of the flavone, apigenin on bone cells were studied. We first show that apigenin inhibits tumor necrosis factor alpha (TNFalpha)- and interferon gamma (IFNgamma)-induced secretion of several osteoclastogenic cytokines from MC3T3-E1 mouse calvarial osteoblast cell line. Ligands of the TNF receptor family constitute the most potent osteoclastic cytokines. In MC3T3-E1 cells, apigenin dose-dependently (from 5 to 20 microM) inhibits TNFalpha-induced production of the osteoclastogenic cytokines, IL-6 (interleukin-6), RANTES (regulated upon activation, normal T cell-expressed and -secreted), monocyte chemoattractant protein-1 (MCP-1) and MCP-3. In addition, apigenin inhibits IFNgamma-stimulated secretion of monokines, CXCL-9, and -10 in MC3T3-E1 cells. Next, we show that apigenin strongly inhibits differentiation of 3T3-L1 preadipocytes to adipocytes with attendant inhibition of adipocyte differentiation-induced IL-6, MCP-1, and leptin production. Inhibition of adipogenic differentiation by apigenin could be due to induction of osteogensis as it robustly upregulates mRNA levels of bone morphogenetic protein-6 (BMP-6). Finally, the presence of apigenin inhibited osteoclast differentiation from the RAW 264.7 cell line by reducing receptor activator of nuclear factor kappa ligand (RANKL)-induced expression of tartrate-resistant acid phosphatase (TRAP), RANK, and calcitonin receptor but not CCR1, resulting in the inhibition of multinucleated osteoclast formation. Similarly, apigenin inhibited expression of the osteoclast differentiation markers TRAP, RANK, and c-Fms in osteoclast precursor cells obtained from mouse bone marrow following treatment with RANKL and macrophage colony stimulating factor (MCSF). Furthermore, apigenin induced apoptosis of mature osteoclasts obtained from rabbit long bone and inhibited bone resorption. In all instances, a structurally related compound, flavone had no significant effect. These data suggest that apigenin has multiple effects on all three bone cells that could prevent bone loss in vivo.
Insights
Apigenin, a natural flavone, prevents bone loss by inhibiting osteoclast formation and activity. It also affects osteoblast and adipocyte cells, suggesting broad benefits for bone health.
Area of Science:
- Biochemistry
- Cell Biology
- Bone Physiology
Background:
- Osteoporosis is a significant health concern characterized by bone loss.
- Cytokines like TNFalpha and IFNgamma play critical roles in bone remodeling and inflammation.
- Flavonoids, such as apigenin, are being investigated for their potential therapeutic effects.
Purpose of the Study:
- To investigate the physiological effects of apigenin on bone cells.
- To determine if apigenin can inhibit osteoclastogenic cytokine production.
- To assess apigenin's impact on osteoblast and adipocyte differentiation and osteoclast formation.
Main Methods:
- MC3T3-E1 osteoblast cell line treated with TNFalpha and IFNgamma.
- 3T3-L1 preadipocyte differentiation assays.
- RAW 264.7 cell line and primary mouse bone marrow cells treated with RANKL and MCSF.
- Apigenin treatment at varying concentrations (5-20 microM).
- Analysis of cytokine secretion, gene expression (mRNA), cell differentiation, apoptosis, and bone resorption.
Main Results:
- Apigenin inhibited TNFalpha-induced secretion of IL-6, RANTES, MCP-1, and MCP-3 in osteoblasts.
- Apigenin reduced IFNgamma-stimulated secretion of CXCL-9 and -10.
- Apigenin inhibited adipogenic differentiation of 3T3-L1 cells and upregulated BMP-6 mRNA.
- Apigenin suppressed RANKL-induced osteoclast differentiation markers (TRAP, RANK, c-Fms) and osteoclast formation.
- Apigenin induced apoptosis of mature osteoclasts and inhibited bone resorption.
Conclusions:
- Apigenin exhibits multiple beneficial effects on osteoblasts, adipocytes, and osteoclasts.
- Apigenin's inhibition of osteoclastogenesis and promotion of osteogenesis suggest potential for preventing bone loss.
- These findings highlight apigenin as a promising therapeutic agent for bone diseases.
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