Antioxidants, like coenzyme Q10, selenite, and curcumin, inhibited osteoclast differentiation by suppressing reactive oxygen species generation.
Coenzyme Q10 (CoQ10), selenium, and curcumin are known to be powerful antioxidants. Osteoclasts are capable of resorbing mineralized bone and excessive bone resorption by osteoclasts causes bone loss-related diseases. During osteoclast differentiation, the reactive oxygen species (ROS) acts as a secondary messenger on signal pathways. In this study, we investigated whether antioxidants can inhibit RANKL-induced osteoclastogenesis through suppression of ROS generation and compared the relative inhibitory activities of CoQ10, sodium selenite, and curcumin on osteoclast differentiation. We found that antioxidants markedly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells in both bone marrow-derived monocytes (BMMs) and RAW 264.7 cells. Antioxidants scavenged intracellular ROS generation within osteoclast precursors during RANKL-stimulated osteoclastogenesis. These also acted to significantly suppress the gene expression of NFATc1, TRAP, and osteoclast-associated immunoglobulin-like receptor (OSCAR), which are genetic markers of osteoclast differentiation in a dose-dependent manner. These antioxidants also suppressed ROS-induced IκBα signaling pathways for osteoclastogenesis. Specially, curcumin displayed the highest inhibitory effect on osteoclast differentiation when concentrations were held constant. Together, CoQ10, selenite, and curcumin act as inhibitors of RANKL-induced NFATc1 which is a downstream event of NF-κB signal pathway through suppression of ROS generation, thereby suggesting their potential usefulness for the treatment of bone disease associated with excessive bone resorption.
Moon HJ, Ko WK, Han SW, Kim DS…
Biochem. Biophys. Res. Commun. Feb 2012
Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway.
Osteoclasts, derived from hemopoietic progenitors of the monocyte/macrophage lineage, have a unique role in bone resorption, and are considered a potential therapeutic target in the treatment of such pathologic bone diseases as osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we demonstrate that curcumol, one of the major components of the essential oil of Rhizoma Curcumae, exhibits an inhibitory effect on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation with both bone marrow-derived macrophages and RAW264.7 cells in a dose-dependent manner. In addition, RANKL-induced mRNA expression of osteoclast-specific genes, such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K, is prominently reduced in the presence of curcumol. Furthermore, the molecular mechanism of action was investigated, and curcumol inhibited osteoclastogenesis by specifically impairing RANKL-induced c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling, which was further identified in rescue studies by means of anisomycin, a JNK signaling-specific activator. Taken together, these findings suggest that curcumol suppresses RANKL-induced osteoclast differentiation through the JNK/AP-1 signaling pathway, and may be useful as a therapeutic treatment for bone resorption-associated diseases.
Yu M, Chen X, Lv C, Yi X…
Biochem. Biophys. Res. Commun. Apr 2014
A synergistic bone sparing effect of curcumin and alendronate in ovariectomized rat.
The purpose of this study was to evaluate the therapeutic effects of combination therapy with curcumin and alendronate on bone remodeling after ovariectomy in rats.
Eighty female Sprague-Dawley rats underwent either a sham operation (the sham group) or bilateral ovariectomy (OVX). The ovariectomized animals were randomly distributed amongst four groups: untreated OVX group, curcumin-administered group, alendronate-administered group, and the combination therapy group. At 8 and 12 weeks after surgery, rats from each of the groups were euthanized. Serum biochemical markers of bone turnover, including osteocalcin and alkaline phosphatase (ALP), and the telopeptide fragment of type I collagen C-terminus (CTX) were analyzed. Bone histomorphometric parameters of the 4th lumbar vertebrae were determined by micro-computed tomography (CT). In addition, mechanical strength was determined by a three-point bending test.
Serum biochemical markers of bone turnover in the experiment groups (curcumin administered group, alendronate administered group, and the combination therapy group) were significantly lower than in the untreated OVX group (p < 0.05). The combination therapy group had lower ALP and CTX-1 concentrations at 12 weeks, which were statistically significant compared with the curcumin only and the alendronate only group (p < 0.05). The combination therapy group had a significant increase in BMD at 8 weeks and Cr.BMD at 12 weeks compared with the curcumin-only group (p = 0.005 and p = 0.013, respectively). The three point bending test showed that the 4th lumbar vertebrae of the combination therapy group had a significantly greater maximal load value compared to that of the curcumin only and the alendronate only group (p < 0.05).
The present study demonstrated that combination therapy with a high dose of curcumin and a standard dose of alendronate has therapeutic advantages over curcumin or alendronate monotherapy, in terms of the synergistic antiresorptive effect on bone remodeling, and improving bone mechanical strength.
Cho DC, Kim KT, Jeon Y, Sung JK
Acta Neurochir (Wien) Dec 2012
Effects of curcumin on the proliferation and mineralization of human osteoblast-like cells: implications of nitric oxide.
Curcumin (diferuloylmethane) is found in the rhizomes of the turmeric plant (Curcuma longa L.) and has been used for centuries as a dietary spice and as a traditional Indian medicine used to treat different conditions. At the cellular level, curcumin modulates important molecular targets: transcription factors, enzymes, cell cycle proteins, cytokines, receptors and cell surface adhesion molecules. Because many of the curcumin targets mentioned above participate in the regulation of bone remodeling, curcumin may affect the skeletal system. Nitric oxide (NO) is a gaseous molecule generated from L-arginine during the catalization of nitric oxide synthase (NOS), and it plays crucial roles in catalization and in the nervous, cardiovascular and immune systems. Human osteoblasts have been shown to express NOS isoforms, and the exact mechanism(s) by which NO regulates bone formation remain unclear. Curcumin has been widely described to inhibit inducible nitric oxide synthase expression and nitric oxide production, at least in part via direct interference in NF-κB activation. In the present study, after exposure of human osteoblast-like cells (MG-63), we have observed that curcumin abrogated inducible NOS expression and decreased NO levels, inhibiting also cell prolifieration. This effect was prevented by the NO donor sodium nitroprusside. Under osteogenic conditions, curcumin also decreased the level of mineralization. Our results indicate that NO plays a role in the osteoblastic profile of MG-63 cells.
Moran JM, Roncero-Martin R, Rodriguez-Velasco FJ, Calderon-Garcia JF…
Int J Mol Sci 2012
PMID: 23443113 | Free Full Text
Therapeutic advantages of treatment of high-dose curcumin in the ovariectomized rat.
Although curcumin has a protective effect on bone remodeling, appropriate therapeutic concentrations of curcumin are not well known as therapeutic drugs for osteoporosis. The purpose of this study was to compare the bone sparing effect of treatment of low-dose and high-dose curcumin after ovariectomy in rats.
Forty female Sprague-Dawley rats underwent either a sham operation (the sham group) or bilateral ovariectomy (OVX). The ovariectomized animals were randomly distributed among three groups; untreated OVX group, low-dose (10 mg/kg) curcumin administered group, and high-dose (50 mg/kg) curcumin group. At 4 and 8 weeks after surgery, serum biochemical markers of bone turnover were analyzed. Bone histomorphometric parameters of the 4th lumbar vertebrae were determined by micro-computed tomography (CT). In addition, mechanical strength was determined by a three-point bending test.
High-dose curcumin group showed significantly lower osteocalcin, alkaline phosphatase, and the telopeptide fragment of type I collagen C-terminus concentration at 4 and 8 weeks compared with the untreated OVX group as well as low-dose curcumin group. In the analyses of micro-CT scans of 4th lumbar vertebrae, the high-dose curcumin treated group showed a significant increase in bone mineral densities (p=0.028) and cortical bone mineral densities (p=0.036) compared with the low-dose curcumin treated group. Only high-dose curcumin treated group had a significant increase of mechanical strength compared with the untreated OVX group (p=0.015).
The present study results demonstrat that a high-dose curcumin has therapeutic advantages over a low-dose curcumin of an antiresorptive effect on bone remodeling and improving bone mechanical strength.
Cho DC, Jung HS, Kim KT, Jeon Y…
J Korean Neurosurg Soc Dec 2013
PMID: 24527187 | Free Full Text
Dosage effects of curcumin on cell death types in a human osteoblast cell line.
Curcumin, the yellow pigment of Curcuma longa, is known to have antioxidant and anti-inflammatory properties, as well as their ability to either induce or prevent cell apoptosis. However, the precise molecular mechanisms of these effects are unknown. Here, we demonstrate that curcumin can induce apoptotic changes, including JNK activation, caspase-3 activation, and cleavage of PARP and PAK2, at treatment concentrations lower than 25 microM in human osteoblast cells. In contrast, treatment with 50-200 microM of curcumin does not induce apoptosis, but rather triggers necrotic cell death in human osteoblasts. Using the cell permeable dye 2′,7′-dichlorofluorescin diacetate (DCF-DA) as an indicator of reactive oxygen species (ROS) generation, we found that while treatment with 12.5-25 microM curcumin directly increased intracellular oxidative stress, 50-200 microM curcumin had far less effect. Pretreatment of cells with N-acetyl cysteine or alpha-tocopherol, two well known ROS scavengers, attenuated the intracellular ROS levels increases and converted the apoptosis to necrosis induced by 12.5-25 microM curcumin. Moreover, we observed a dose-dependent decrease in intracellular ATP levels after treatment of osteoblast cells with curcumin and pretreatment of cells with antimycin or 2-deoxyglucose to cause ATP depletion significantly converted 12.5-25 microM curcumin-induced apoptosis to necrosis, indicating that ATP (a known mediator of apoptotic versus necrotic death) is most likely involved in the switching mechanism. Overall, our results signify that curcumin dosage treatment determines the possible effect on ROS generation, intracellular ATP levels, and cell apoptosis or necrosis in osteoblast cells.
Chan WH, Wu HY, Chang WH
Food Chem. Toxicol. Aug 2006
Effects of curcumin on the skeletal system in rats.
There is increasing interest in the discovery of natural compounds that could favorably affect the skeletal system. Curcumin is a constituent of turmeric, a plant which has been used for centuries as a dietary spice and a traditional Indian medicine. Curcumin has been reported to affect differentiation, activity and the lifespan of osteoblasts and osteoclasts in vitro. The aim of the present study was to investigate the effects of curcumin on the skeletal system of rats in vivo. Curcumin (10 mg/kg, po daily) was administered for four weeks to normal (non-ovariectomized) and bilaterally ovariectomized (estrogen-deficient) three-month-old female Wistar Cmd:(WI)WU rats. Ovariectomy was performed seven days before the start of curcumin administration. Bone mass, mineral and calcium content, macrometric and histomorphometric parameters, as well as the mechanical properties of the bone, were examined. Serum total cholesterol and estradiol levels were also determined. In rats with normal estrogen levels, curcumin decreased serum estradiol level and slightly increased cancellous bone formation, along with decreased mineralization. Estrogen deficiency induced osteoporotic changes in the skeletal system of the ovariectomized control rats. In ovariectomized rats, curcumin decreased body mass gain and serum total cholesterol level, slightly improved some bone histomorphometric parameters impaired by estrogen deficiency, but did not improve bone mineralization or mechanical properties. In conclusion, the results of the present in vivo study in rats did not support the hypothesis that curcumin, at doses that are readily achievable through dietary intake, could be useful for the prevention or treatment of osteoporosis.
Folwarczna J, Zych M, Trzeciak HI
PMID: 21098873 | Free Full Text
Curcumin protects against ovariectomy-induced bone loss and decreases osteoclastogenesis.
Curcumin has anti-oxidative activity. In view of the increasing evidence for a biochemical link between increased oxidative stress and reduced bone density we hypothesized that curcumin might increase bone density by elevating antioxidant activity in some target cell type. We measured bone density by Micro-CT, enzyme expression levels by quantitative PCR or enzyme activity, and osteoclast (OC) formation by tartrate-resistant acid phosphatase staining. The bone mineral density of the femurs of curcumin-administered mice was significantly higher than that of vehicle-treated mice after ovariectomy (OVX) and this was accompanied by reduced amounts of serum collagen-type I fragments, which are markers of bone resorption. Curcumin suppressed OC formation by increasing receptor activator of nuclear factor-κB ligand (RANKL)-induced glutathione peroxidase-1, and reversed the stimulatory effect of homocysteine, a known H(2) O(2) generator, on OC formation by restoring Gpx activity. Curcumin generated an aberrant RANKL signal characterized by reduced expression of nuclear factor of activated T cells 2 (NFAT2) and attenuated activation of mitogen-activated protein kinases (ERK, JNK, and p38). Curcumin thus inhibited OVX-induced bone loss, at least in part by reducing osteoclastogenesis as a result of increased antioxidant activity and impaired RANKL signaling. These findings suggest that bone loss associated with estrogen deficiency could be attenuated by curcumin administration.
Kim WK, Ke K, Sul OJ, Kim HJ…
J. Cell. Biochem. Nov 2011
The ovariectomized, mature rat model of postmenopausal osteoporosis: an assessment of the bone sparing effects of curcumin.
Identification of natural health products that might benefit skeletal health could reduce the negative impact of osteoporotic bone fractures upon society. The objectives of this study were to evaluate an animal model of postmenopausal osteoporosis and to search for evidence that curcumin reduces bone mineral losses in a dose-dependent manner when endogenous estrogen levels are reduced. Bone mineral density was measured at the spine, femur and whole body before and at 2, 4 and 6 months after ovariectomy in each of 40 mature rats. Serum osteocalcin and C-telopeptide were measured as indicators of bone formation and resorption rates. Femoral compressive strength was measured at 6 months. Ovariectomy alone resulted in loss of mineral from the spine (p<0.005) and an increase in osteocalcin levels (p<0.05). At the same time, there was an increase in energy to fracture (p<0.01) due to an increased bone size. When ovariectomized animals were given etidronate there was no loss of mineral from the spine, the size of the femur increased (p<0.005), C-telopeptide levels were reduced (p<0.001) and femoral compressive strength increased (p<0.025). Administration of curcumin to ovariectomized animals resulted in changes that were intermediate between those produced by etidronate and by ovariectomy alone. The increase in femur size produced by the highest dose of curcumin was statistically significant (p< 0.01) and curcumin administration resulted in a significant, dose dependent, increase in energy to fracture. Curcumin produces beneficial changes in bone turnover and increases in bone strength using the ovariectomized mature rat model of postmenopausal osteoporosis.
French DL, Muir JM, Webber CE
Phytomedicine Dec 2008
Screening of Korean medicinal plants for possible osteoclastogenesis effects in vitro.
Bone undergoes continuous remodeling through bone formation and resorption, and maintaining the balance for skeletal rigidity. Bone resorption and loss are generally attributed to osteoclasts. Differentiation of osteoclasts is regulated by receptor activator of nuclear factor NF-kB ligand (RANKL), a member of tumor necrosis factor family. When the balance is disturbed, pathological bone abnormality ensues. Through the screening of traditional Korean medicinal plants, the effective molecules for inhibition and stimulation of RANKL-induced osteoclast differentiation in mouse bone marrow macrophages were identified. Among 222 methanol extracts, of medicinal plants, 10 samples exhibited ability to induce osteoclast differentiation. These include Dryobalanops aromatica, Euphoria longana, Lithospermum erythrorhizon, Prunus mume, Prunus nakaii, and Polygonatum odoratum. In contrast, Ailanthus altissima, Curcuma longa, Solanum nigrum, Taraxacum platycarpa, Trichosanthes kirilowii, and Daphne genkwa showed inhibitory effects in RANKL-induced osteoclast differentiation.
Youn YN, Lim E, Lee N, Kim YS…
Genes Nutr Feb 2008
PMID: 18850234 | Free Full Text