Resveratrol enhances proliferation and osteoblastic differentiation in human mesenchymal stem cells via ER-dependent ERK1/2 activation (original) (raw)
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Toxicology in Vitro, 2006
The purpose of this study was to investigate the in vitro effects of resveratrol (RSVL) and cyclosporin A (CsA) on proliferation and osteoblastic differentiation of mouse bone marrow-derived mesenchymal stem cell (BMSC) cultures. Application of RSVL (10 À8 -10 À6 mol l À1 ) resulted in a dose-dependent increase in [ 3 H]-thymidine incorporation, alkaline phosphatase (ALP) activity and calcium deposition of BMSCs cultures, which was accompanied with the increase of NO production and cGMP content. Concurrent treatment with the estrogen receptor antagonist ICI182,780 (10 À7 mol l À1 ) or the NO synthase inhibitor, N x -nitro-L-arginine methyl ester (6 · 10 À3 mol l À1 ) abolished the RSVL (10 À6 mol l À1 )-induced increase in NO production and cGMP content and eliminated the RSVL-induced increase in proliferation and osteoblastic differentiation of BMSCs. In contrast, CsA (10 À6 -10 À5 mol l À1 ) dosedependently decreased [ 3 H]-thymidine incorporation, ALP activity and calcium deposition of BMSCs cultures, which was accompanied with the reduction of NO production in the conditioned media. Concurrent treatment with RSVL (10 À6 mol l À1 ) significantly reversed the CsA (3 · 10 À6 mol l À1 )-mediated decrease in NO production and restored the proliferation and differentiation potential of BMSCs. Our data suggest that (1) the NO/cGMP pathway may play an important role in both RSVL-induced and CsA-inhibited proliferation and osteoblastic differentiation of mouse BMSCs, and (2) RSVL may act through an ER/NO/cGMP pathway to reverse the inhibitory effect of CsA on BMSC cultures. Taken together, the data suggest that RSVL may prevent osteoporosis induced by CsA.
Osteogenic Effects of a Potent Src-over-Abl-Selective Kinase Inhibitor in the Mouse
Journal of Pharmacology and Experimental Therapeutics, 2011
Src-null mice have higher bone mass because of decreased bone resorption and increased bone formation, whereas Ablnull mice are osteopenic, because of decreased bone formation. Compound I, a potent inhibitor of Src in an isolated enzyme assay (IC 50 0.55 nM) and a Src-dependent cell growth assay, with lower activity on equivalent Abl-based assays, potently, but biphasically, accelerated differentiation of human mesenchymal stem cells to an osteoblast phenotype (1-10 nM). Compound I (Ն0.1 nM) also activated osteoblasts and induced bone formation in isolated neonatal mouse calvariae. Compound I required higher concentrations (100 nM) to inhibit differentiation and activity of osteoclasts. Transcriptional profiling (TxP) of calvaria treated with 1 M compound I revealed downregulation of osteoclastic genes and up-regulation of matrix genes and genes associated with the osteoblast phenotype, confirming compound I's dual effects on bone resorption and formation. In addition, calvarial TxP implicated calcitonin-related polypeptide,  (-CGRP) as a potential mediator of compound I's osteogenic effect. In vivo, compound I (1 mg/kg s.c.) increased vertebral trabecular bone volume 21% (microcomputed tomography) in intact female mice. Increased trabecular volume was also detected histologically in a separate bone, the femur, particularly in the secondary spongiosa (100% increase), which underwent a 171% increase in bone formation rate, a 73% increase in mineralizing surface, and a 59% increase in mineral apposition rate. Similar effects were observed in ovariectomized mice with established osteopenia. We conclude that the Src inhibitor compound I is osteogenic, presumably because of its potent stimulation of osteoblast differentiation and activation, possibly mediated by -CGRP.
International Journal of Molecular Sciences, 2020
Indoxyl sulfate (IS), a uremic toxin derived from dietary tryptophan metabolism by the gut microbiota, is an endogenous aryl hydrocarbon receptor (AhR) agonist and a key player in bone remodeling. Resveratrol (RSV), an AhR antagonist, plays a protective role in shielding against AhR ligands. Our study explored the impact of IS on osteoblast differentiation and examined the possible mechanism of IS in controlling the expression of osteoblastogenesis markers through an in-depth investigation of AhR signaling. In vivo, we found histological architectural disruption of the femoral bones in 5/6 nephrectomies of young adult IS exposed mice, including reduced Runx2 antigen expression. RSV improved the diaphysis architecture, Runx2 expression, and trabecular quality. In vitro data suggest that IS at 500 and 1000 μM disturbed osteoblastogenesis through suppression of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways, which were found to be downstream of AhR. RSV proved to amel...
Biomedicines
Resveratrol (RSV) (3,5,4′-trihydroxystilbene) is a stilbene found in abundance in berry fruits, peanuts, and some medicinal plants. It has a diverse range of pharmacological activities, underlining the significance of illness prevention and health promotion. The purpose of this review was to delve deeper into RSV’s bone-protective properties as well as its molecular mechanisms. Several in vivo studies have found the bone-protective effects of RSV in postmenopausal, senile, and disuse osteoporosis rat models. RSV has been shown to inhibit NF-κB and RANKL-mediated osteoclastogenesis, oxidative stress, and inflammation while increasing osteogenesis and boosting differentiation of mesenchymal stem cells to osteoblasts. Wnt/β-catenin, MAPKs/JNK/ERK, PI3K/AKT, FoxOs, microRNAs, and BMP2 are among the possible kinases and proteins involved in the underlying mechanisms. RSV has also been shown to be the most potent SIRT1 activator to cause stimulatory effects on osteoblasts and inhibitory e...
Resveratrol inhibits proliferation and promotes apoptosis of osteosarcoma cells
European Journal of Pharmacology, 2009
Osteoblasts play a fundamental role in determining bone structure and function. These cells originate from mesenchymal stem cells (MSCs) and through proliferation and differentiation develop into preosteoblasts and then into mature cells. Most of these cells undergo apoptosis before reaching their terminal differentiated stages of either osteocytes or bone lining cells. These processes, i.e. proliferation, differentiation, and apoptosis, are affected by systemic hormones and local factors. In addition, there are exogenous regulators, which can either be natural substances or synthetic compounds. This thesis describes investigations of the effects of several selected factors on proliferation, differentiation, and apoptosis of osteoblastic cells. The thesis is based on four papers: In the first paper, the effects of Sirt1 regulators, resveratrol (RSV), nicotinamide (NAM), and isonicotinamide (INM), on the commitment of mesenchymal stem cells (MSC) were studied. We found that the Sirt1 activators, RSV and INM, inhibited adipocyte formation and enhanced osteoblast differentiation, while the inhibitor NAM had the opposite effect. In the second paper, osteoblastic cells from different origins, mouse, rat, and human, were treated with 1α,25(OH) 2 D 3 and its analogue, 2-methylene-19-nor-(20S)-1α,25(OH) 2 D 3 (2MD). Species-dependent effects on cell growth and alkaline phosphatase (ALP) activity were clearly seen. In the third paper, we found that the expression of Interleukin-6 (IL-6) receptor increased during osteoblast differentiation. IL-6 acted as a differentiation accelerator in the early stage and an apoptosis inducer at late mature stage. In the forth paper, the effects of Sirt1 activators, RSV and INM, on proliferation and apoptosis of human osteosarcoma (OS) cells were studied. We found an inhibitory effect of Sirt1 activators on OS cells and showed a synergism between RSV and L-asparaginase (ASNase), which is a selective nutritional restrictor. In summary, the work presented in this thesis provides new information about the effects of two osteoblast differentiation regulators, 1α,25(OH) 2 D 3 and IL-6. Additionally, certain compounds affecting Sirt1 activity were found to influence osteoblast differentiation; RSV and INM which increase Sirt1 activity also had a profoundly negative effect on growth of OS cells in vitro. LIST OF PUBLICATIONS This thesis is based on the work of the following papers. They are referred to by their Roman numerals. I. Bäckesjö CM, Li Y, Lindgren U, and Haldosén LA. Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. J Bone Miner Res 2006; 21: 993-1002. II. Li Y, Bäckesjö CM, Haldosén LA, and Lindgren U. Species difference exists in the effects of 1α,25(OH)2D3 and its analogue 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 (2MD) on osteoblastic cells. Accepted Manuscript, The Journal of Steroid Biochemistry and Molecular Biology.
Journal of Cellular Biochemistry, 2012
Osteoporosis is a reduction in skeletal mass due to an imbalance between bone formation and bone resorption. Therefore, the identification of specific stimulators of bone formation is of therapeutic significance in the treatment of osteoporosis. Salicylideneamino-2-thiophenol (Sal-2) consists of two benzene rings, has been reported to possess antioxidant activity, and is an effective remedy for fever and rheumatic diseases. However, until now the effects of osteoblastic bone formation by Sal-2 were unknown. In this study, we investigated the effects of Sal-2 on osteogenic differentiation of multipotent bone marrow stromal stem cells by alizarin red S staining for osteogenic differentiation, RT-PCR and western blot for alkaline phosphatase (ALP) activity and signaling pathways, FACS analysis and immunofluorescence staining for CD44 and CD51 expression, calcium assays, and immunofluorescence staining for signaling pathways. We found that Sal-2 enhanced the osteogenic differentiation of multipotent bone marrow stromal stem cells. Sal-2 treatment induced the expression and activity of ALP, and enhanced the levels of CD44 and CD51 expression as well as Ca 2þ content, in multipotent bone marrow stromal stem cells. Moreover, we found that Sal-2induced osteogenic differentiation and expression of osteogenesis-related molecules involve the activation of the MAPK and nuclear factor-kB pathways. Our findings provide insight into both the mechanism and effects of Sal-2 on osteogenic differentiation and demonstrate that Sal-2 may be a beneficial adjuvant in stimulating bone formation in osteoporotic diseases.
Regulation of Osteoblastic Differentiation: A Concept Note
American Journal of Life Sciences
Bone is endocrine metabolic organ which maintains its integrity through the process of bone remodeling controlled by several local and systemic factors. Any perturbation in the bone remodeling leads to development of osteoporosis which is mostly age related but can be premature as well. Several therapies have come up to treat osteoporosis including bisphosphonates but due to side effects natural compounds are looked like resveratrol which has estrogenic property depending upon the type of tissue it is acting upon. Resveratrol has stimulatory effect on bone cells by modulating the process of differentiation through change in the expression levels of osteoblastic genes through estrogen receptors.
Control of the Osteoblast Lineage by Mitogen-Activated Protein Kinase Signaling
Current Molecular Biology Reports, 2017
Purpose of the review-This review will provide a timely assessment of MAP kinase actions in bone development and homeostasis with particular emphasis on transcriptional control of the osteoblast lineage Recent findings-ERK and p38 MAP kinases function as transducers of signals initiated by the extracellular matrix, mechanical loading, TGF-β, BMPs and FGF2. MAPK signals may also affect and/or interact with other important pathways such as WNT and HIPPO. ERK and p38 MAP kinase pathways phosphorylate specific osteogenic transcription factors including RUNX2, Osterix, ATF4 and DLX5. For RUNX2, phosphorylation at specific serine residues initiates epigenetic changes in chromatin necessary for decondensation and increased transcription. MAPK also suppresses marrow adipogenesis by phosphorylating and inhibiting PPARγ, which may explain the well-known relationship between reduced skeletal loading and marrow fat accumulation. Summary-MAPKs transduce signals from the extracellular environment to the nucleus allowing bone cells to respond to changes in hormonal/growth factor signaling and mechanical loading thereby optimizing bone structure to meet physiological and mechanical needs of the body.
Cytokine, 2003
Bone morphogenetic protein-6 (BMP-6) is a potent inducer of osteogenic differentiation and its expression is stimulated by 17bestradiol. The existence of a regulatory loop between sex steroids and BMP-6 is therefore reasonable to hypothesize. Here we determined whether the sex steroids 17b-estradiol and dihydrotestosterone, and the phytoestrogen resveratrol can modulate BMP-6induced alkaline phosphatase activity and osteocalcin expression. Mesenchymal cells of murine (osteoblastic MC3T3-E1 cells, preadipogenic ST2 cells, prechondrogenic ATDC5 cell) and human origin (osteosarcoma SaOS and HOS cells, primary bone marrow stromal cells) were cultured in the presence of recombinant BMP-6 under serum-free conditions. BMP-6 dose-, and timedependently increased alkaline phosphatase activity in murine cell lines, but not in human cells. Osteocalcin expression was also increased upon stimulation with BMP-6. The presence of 17b-estradiol, dihydrotestosterone, and resveratrol had no effect on BMP-6-induced alkaline phosphatase activity and osteocalcin expression. These data suggest that osteogenic differentiation in response to BMP-6 occurs independent of steroid hormones and resveratrol in mesenchymal cells that express basal receptor levels.
BMB Reports
Estrogen-related receptor (ERR), a member of the orphan nuclear receptor family, is a key mediator in cellular metabolic processes and energy homeostasis. Therefore, ERR has become an attractive target for treating diverse metabolic disorders. We recently reported that ERR acts as a negative regulator of osteoclastogenesis induced by receptor activator of nuclear factor-B ligand (RANKL). In the present study, we explored the effects of an ERR-specific modulator, GSK5182, on ERR-regulated osteoclast differentiation and survival. Interestingly, GSK5182 increased ERR protein levels much as does GSK4716, which is an ERR agonist. GSK5182 inhibited osteoclast generation from bone-marrow-derived macrophages without affecting cytotoxicity. GSK5182 also attenuated RANKL-mediated expression of c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), pivotal transcription factors for osteoclastogenesis. Arrested osteoclast differentiation was associated with reduced RANK expression, but not with the M-CSF receptor, c-Fms. GSK5182 strongly blocked the phosphorylation of IB, c-Jun N-terminal kinase, and extracellular signal-regulated kinase in response to RANKL. GSK5182 also suppressed NF-B promoter activity in a dose-dependent manner. In addition to osteoclastogenesis, GSK5182 accelerated osteoclast apoptosis by caspase-3 activation. Together, these results suggest that GSK5182, a synthetic ERR modulator, may have potential in treating disorders related to bone resorption. [BMB Reports 2021; 54(5): 266-271]