Abstract
Butein is a phytochemical that belongs to the chalcone family of flavonoids and has antitumor, anti-inflammatory, and anti-osteoclastic bone resorption activities. This study aims to investigate the effects of butein on the differentiation potential of mouse primary bone marrow-derived mesenchymal stem cells (mBMSCs) into osteoblast and adipocyte lineages. Primary cultures of mBMSCs are treated with different doses of butein during its differentiation. Osteoblast differentiation is assessed by alkaline phosphatase (ALP) activity quantification and Alizarin red staining for matrix mineralization, while adipogenesis is assessed by quantification of lipid accumulation using Oil Red O staining. Osteoblastic and adipocytic gene expression markers are determined by quantitative real-time PCR (qPCR). Western blot analysis is used to study the activation of extracellular signal-regulated kinase (ERK1/2). Interestingly, butein promotes the lineage commitment of mBMSCs into osteoblasts, while suppressing their differentiation into adipocytes in a dose-dependent manner. A similar effect of butein is confirmed in human (h) primary BMSCs. Occurring at the molecular level, butein significantly upregulates the mRNA expression of osteoblast-related genes, while downregulating the expression of adipocyte-related genes. The mechanism of butein-induced osteogenesis is found to be mediated by activating the ERK1/2 signaling pathway. To conclude, we identify butein as a novel nutraceutical compound with an osteo-anabolic activity to promote the lineage commitment of BMSCs into osteoblast versus adipocyte. Thus, butein can be a plausible therapeutic drug for enhancing bone formation in osteoporotic patients.
Highlights
Bone integrity is retained by a dynamic process of bone remodeling, which maintains the balance between bone formation by osteoblasts and bone resorption by osteoclasts
We examined the cytotoxicity of butein on primary cultures of mBMSCs
To get insight into the mechanism underlying the stimulatory effect of butein on osteogenesis, Shown in Figure 2D, treatment of mBMSCs with butein during osteogenesis at early and we examined the effect of butein on mBMSCs at different stages during osteoblast-lineage middle stages showed a significant increase in alkaline phosphatase (ALP) activity levels, while late treatment of commitment
Summary
Bone integrity is retained by a dynamic process of bone remodeling, which maintains the balance between bone formation by osteoblasts and bone resorption by osteoclasts. Osteoblasts are resultant from bone marrow-derived mesenchymal stem cells (BMSCs), while osteoclasts are derived from hematopoietic stem cells in bone marrow [1,2]. An excess bone resorption rate and/or dysregulation of bone formation results in osteoporosis [3,4,5]. The treatment for osteoporosis is mainly based on anti-resorptive drugs that target osteoclast-mediated bone resorption such as bisphosphonates, calcitonin, estrogen and Denosumab, a humanized monoclonal antibody against the receptor-activator of nuclear factor kappa-b ligand (RANKL) [6,7]. There are few existing anabolic bone therapeutics for osteoporosis including, parathyroid hormone (PTH) and, recently, Romosozumab, a humanized-neutralizing monoclonal antibody against sclerostin, an antagonist of Wnt signaling secreted by an osteocyte [8,9,10,11]. There is a need for developing new anabolic bone drugs with safe processes to directly target the stimulation of bone formation in bone-loss related diseases
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