There are two main specialized cells involved in the bone-remodeling process, osteoblasts OBs and osteoclasts OCs , which are responsible for new bone formation and aged bone resorption, respectively.

The proper balancing act between bone resorption by OCs and bone deposition by OBs is essential for the active and dynamic process of bone remodeling. Polyphenols are a group of phytochemicals that are found in plants. Due to their bioactive components, like flavonoids, phenolic acids, and stilbenes, medicinal plants have long been pursued in the drug development process.

Many medicinal plant extracts have been found to improve bone health. To provide more applicable preclinical research results, scientists have concentrated on developing in vitro models of bone cells by utilizing cell lines or primary cells.

However, OBs and OCs do not act independently of one another, and various communication pathways between them have been discovered.

This review summarizes the relevant data from existing studies on the effects of polyphenols on OBs and OCs using monocultures; these studies can be further enriched using co-culture, which represents an experimental system closer to the in vivo conditions than monoculture, allowing realistic cell— cell interactions.

This information will be valuable for the development of new pharmaceutical and nutraceutical agents to treat and manage bone diseases. Bone remodeling is the dynamic process of bone formation and resorption in vertebrates to maintain bone volume and calcium homeostasis 1 , 2. Osteoclasts OCs and osteoblast OBs are the two main specialized cells involved in the bone remodeling process through which the old or damaged bones are resorbed by OCs bone resorption and new bone is formed by OBs bone formation 3 , 4.

The proper balancing act between bone resorption by OCs and bone deposition by OBs is important in the maintenance of healthy bones 2 , 4.

OBs and OCs work in balance, and a dysregulated interplay or imbalance between these cell types may result in implications on the bone that vary from fractures that do not heal effectively to major conditions, such as osteoporosis or in rare cases, osteopetrosis 5 , 6 , 7 , 8.

Osteoporosis is a silent disease that is often undiagnosed 11 , As the population ages, osteoporosis will become more prevalent and will have a greater influence on clinical, economic, and social outcomes for people of all sexes and ethnicities 11 , The treatment cost of a hip fracture in developing countries, like Malaysia, is expected to increase from Increasing age, female sex, postmenopausal status, hypogonadism or premature ovarian failure, low body mass index, ethnic background, rheumatoid arthritis, low bone mineral density BMD , vitamin D deficiency, low calcium intake, hyperkyphosis, smoking, alcohol abuse, immobilization, and long-term use of certain medications are a few of the factors that can cause osteoporosis Antiresorptive and anabolic therapies have been established for the treatment of osteoporosis using numerous drugs and biomaterials with the aim of activating bone formation or suppressing OC function and survival To provide more applicable preclinical research results, scientists have concentrated on developing in vitro models of bone cells utilizing cell lines or primary cells Studies have been conducted on primary cells, such as primary mouse mesenchymal progenitor cell-derived OBs 17 , 18 , primary human osteoblast Hob cells, and PMBC-derived OCs Cell lines include the human fetal osteoblast cell line hFOB 1.

Because OBs and OCs are important during osteogenesis and remodeling, these cells are used for in vitro studies of bone diseases 23 , These cells do not behave independently of one another, and various communication pathways between them have been discovered Therefore, the complex interactions of OBs and OCs and their precursors during bone remodeling are best studied and understood using co-culture, which may provide more information on the engineering of bone tissues The monoculture model involves only one cell type in a culture medium, whereas the co-culture method includes multiple cell types, which are cultured together in the same medium.

This review summarizes the effects of polyphenols on both OBs and OCs using a monoculture model. Further research on polyphenols should be conducted with the development of a co-culture model as it allows for optimal cell—cell interactions and mimics the in vivo environment more accurately than a monoculture The class of phytochemicals known as polyphenols is present in a variety of plants, including apples, berries, citrus fruit, plums, broccoli, chocolate, tea, and coffees 27 , Phenols hydroxybenzenes , especially polyphenols containing two or more phenol groups , are synthesized by plants; they perform important roles under certain difficult conditions, such as when pathogens are present or when the climate is challenging 28 , Polyphenols can be divided into four significant groups determined by the number and binding structure of the phenol units: flavonoids, stilbenes, lignans, and phenolic acids Figure 1 30 , Flavonoids can be found in edible plants, such as cranberries Vaccinium macrocarpon and apples Malus sylvestris.

Flavonoids can also exist as polymers or aglycons in the seeds of plants Anthocyanins, flavanols, flavanones, flavones, flavonols and isoflavonoids are the main classes of flavonoids Table 1 summarizes the effects of flavonoids on OBs and OCs based on previous studies conducted using the in vitro monoculture model.

Effects of polyphenols on OBs and OCs. Swarnkar et al. Furthermore, h treatment increased mRNA levels of runt-related transcription factor 2 Runx2 , and h treatment increased bone morphogenetic protein 2 Bmp2 , collagen type-1 Col1 , and osteocalcin Bglap , which are important osteogenic gene expression markers In addition to the increase in OB differentiation, AG subsequently increased osteoprotegerin Tnfrsf11b levels after 24 h and 48 h of treatment Tnfrsf11b is a soluble decoy receptor for the nuclear factor-B ligand receptor activator, which is essential for the differentiation of OCs In addition, treatment with nM AG on day 6 decreased mRNA levels of tartrate-resistant acid phosphatase TRAP , c-fos, RANK, and cathepsin K Ctsk Kaempferol [3,5,7-trihydroxy 4-hydroxyphenyl -4 Hbenzopyranone] is a natural flavonoid with a low molecular weight that is present in foods like broccoli, cabbage, beans, tomatoes, strawberries, grapes, and tea Previous studies have shown that kaempferol exhibits antioxidant and anticancer activities in vitro and in vivo Furthermore, it can be applied to the management of osteoporosis.

Wattel et al. OCs were obtained and purified from unfractionated bone cells from long bones of day-old rabbits and were cultured for 48 h before treatment with kaempferol Treatment with 50 µM kaempferol increased the number of apoptotic OCs compared with a control. Another study on murine macrophage RAW In addition, the treatment inhibited the activation of extracellular signal-regulated kinase ERK and c-Jun N-terminal kinase JNK of the mitogen-activated protein kinase MAPK pathway, which subsequently reduced the expression of RANKL, TNF receptor-associated factor 6 TRAF6 , c-Fos, and NFATc1.

Kaempferol-immobilized titanium dioxide TiO 2 increased osteogenic activity in rat bone marrow stromal cells rBMSCs isolated from femurs of 6-week-old female Sprague—Dawley rat femurs The results showed that the calcium deposition of rBMSCs after 7 days on Al-aK was significantly higher than in the control, Al-Ti, and Al-cK samples In addition, calcium deposition in both the Al-aK and Al-cK samples was significantly higher than in the control and Al-Ti sample after 14 days of treatment Furthermore, the mRNA expression of OB-related proteins, such as osteocalcin Bglap , osteonectin Sparc , osteopontin Spp1 , and Alpl in rBMSCs grown on Al-aK and Al-cK was higher than in rBMSCs grown on the control and Al-Ti on day 3 and 7 Another study found that kaempferol stimulated the osteogenic differentiation of cultured OBs by acting through estrogen receptor ER signaling evidenced by the induction effect on pERE-Luc-transfected cultured OBs Primary rat OBs were obtained from calvarial bones from 2-day-old neonatal Sprague—Dawley rats.

In OBs expressing pERE-Luc, 50 µM kaempferol and 17β-estradiol increased luciferase activity in a dose-dependent manner Furthermore, 30 µM kaempferol and 17β-estradiol increased Alpl activity and osteoblastic mineralization However, pre-treatment with ICI , estrogen receptor inhibitor fully blocked kaempferol-induced and 17β-estradiol pERE-Luc activity and Alpl activity, indicating that kaempferol acts via ER activation In addition, kaempferol and 17β-estradiol treatment of OBs significantly increased the transcription of numerous genes of bone differentiation markers, such as Col1 , Sparc , Bglap , Runx2 , and Sp7 ; this transcription was also blocked by pre-treatment of ICI , Another naturally occurring flavonoid is luteolin 3',4',5,7-tetrahydroxyflavone , which typically appears in glycosylated forms in celery, green pepper, perilla leaf, and chamomile tea and as an aglycone in perilla seeds A study on the MG63 OB cell line reported that 10 -6 M luteolin treatment for 24 h enhanced OB-related gene expression, including expression of Runx2 , Alpl , Col1 , Sp7 , and Bglap Luteolin also has an anabolic effect on osteoblastic MC3T3-E1 cells through an estrogen-mediated mechanism For example, luteolin significantly enhanced collagen production in osteoblastic MC3T3-E1 cells at 1 µM , Alpl activity at 0.

However, the effects of luteolin on increasing collagen synthesis and Alpl activity were inhibited by the anti-estrogen drug tamoxifen, indicating that luteolin is involved partly in the mechanism of estrogen action in osteoblastic cells Crasto et al.

The EC 50 for both cells was 1. Luteolin treatment inhibited bone resorption via disruption of OC V-ATPase V-ATPases are recruited to the plasma membranes of polarized, active OCs during bone resorption, where they regulate extracellular acidification Furthermore, luteolin decreased the surface area of the resorption pit, which reduced the overall volume of the pit while inhibiting OC bone resorption without altering OC actin ring formation Flavonoids are the most prevalent phenolic chemicals found in food, whereas stilbenes are rarely found in the human diet 54 , 55 , Flavonoids can be found in plants, such as grapevine, berries, and peanuts Two benzene rings connected by an isopropylene moiety to form a compact ring structure and separated by a double bond define the structure of stilbenes Table 1 shows the effects of stilbenes on OBs and OCs.

Piceatannol 3,3',4,5'-tetrahydroxy-trans-stilbene , or PIC, is found in grapes, passion fruit, white tea, Japanese knotweed, Asian legume, and Korean rhubarb. PIC exhibits antioxidant, antitumor, and anti-inflammatory activities, without toxicity in humans Chang et al.

PIC treatment did not improve cell proliferation but significantly increased Alpl 48 h treatment and Bglap 72 h treatment protein and gene expression at 0. PIC treatment also increased Col1 synthesis 72 h treatment and mineralization 96 h treatment In addition, PIC increased the expression of Bmp2 at both the transcriptional and translational level in a time- 6 — 24 h and dose-dependent manner 1 — 2 µM.

Therefore, PIC treatment can increase the differentiation of MG and hFOB cells from the cell maturation stage of development to the matrix maturation stage PIC also significantly affects OC differentiation and bone resorption OCs were differentiated from RAW PIC significantly reduced TRAP-positive OCs and inhibited OC development in a dose-dependent manner 0, 2.

The treatment also significantly reduced bone resorption pits, increased mature OC apoptosis, and decreased mature OC survival in a dose-dependent manner PIC treatment reduced the mRNA expression of NFATc1, dendritic cell-specific transmembrane protein Dcstamp , Ctsk, matrix metallopeptidase-9 Mmp9 , and TRAP induced by RANKL.

Lignan is found in plants, such as flaxseed, sesame, and seeds of Arctium lappa Table 1 shows the effects of lignan on OBs and OCs.

Gastrodin GSTD , also known as gastrodia glycoside, is a phenolic compound that is found in Gastrodia elata, a well-known Chinese medicine It has been used for many years as an anticonvulsant, analgesic, and sedative agent against vertigo, general paralysis, epilepsy, and tetanus Liu et al.

Their study was conducted on dexamethasone DEX -induced cellular dysfunction of MC3T3-E1 OBs. Furthermore, 7 days of 1—5 µM GSTD treatment significantly increased Alpl activity, which was reduced by DEX In addition, via the NRF2 signaling pathway, GSTD promoted osteogenesis and maintained the balance between adipogenesis Treatment enhanced the expression of bone osteogenic markers, such as Bmp2 , Runx2 , Sp7 , and Bglap In addition, GSTD treatment enhanced the formation of calcium nodules, upregulating OB osteogenic differentiation and enhancing the maturation process of MC3T3-E1 cells Pre-treatment with GSTD for 1 h also significantly reduced DEX-induced apoptosis of OBs An in vitro study conducted by Zhou et al.

OCs were derived from BMM cells via RANKL and M-CSF stimulation. GSTD 2 and 10 µM suppressed RANKL-induced OC differentiation in the early stage of culture day 0—2 in a dose-dependent manner and attenuated OC differentiation at the terminal stage of culture by inhibiting the migration of OCs to resorb into the bone slice Moreover, GSTD reduced the expression of NFATc1 in BMM cells on days 1 — 3, which subsequently reduced the fusion and migration of pre-OCs by downregulating OC-specific gene expression, including the expression of TRAP, Ctsk, and Dcstamp Phenolic acid is another bioactive compound that exists in many plants.

In its structure, hydrogen atoms on benzene rings are replaced by a carboxylic acid group with at least one hydroxyl Benzoic acids gallic, p-hydroxybenzoic, vanillic, and syringic acid and cinnamic acid are the two major phenolic chemicals from which phenolic acid is generated caffeic, ferulic, sinapic, and p-coumaric acids Tannic acid TA is a naturally occurring polyphenol that is found in red wine, beer, coffee, black tea, green tea, grapes, pears, bananas, sorghum, black-eyed peas, lentils, and chocolate TA has been used as a food additive, a medication to treat diarrhea, a local astringent, an antidote for poisoning, and a remedy for burns It also possesses antioxidant, antimutagenic, and anticarcinogenic activities TA treatment is more effective in increasing hFOB 1.

Moreover, treatment of hFOB 1. Compared with cells treated with PAM, TA produced better results in terms of proliferation, morphological alterations, and mineralization In contrast, a study by Steffi et al. The treatment also reduced the OC number measured by total DNA on day 5 of culture Furthermore, the treatment reduced the actin ring formation of OCs The effects of phenolic acid on OBs and OCs are presented in Table 1.

Following consumption of coffee, vegetables, blueberries, and other fruits, a polyphenol molecule called 3 3-hydroxyphenyl propionic acid PPA , a phenolic acid that is generated by the gut microbiota, is released into the bloodstream 69 , The breakdown of chlorogenic acid by the gut microbiota results in the production of PPA, which is absorbed and oxidized in the liver before entering the circulation In addition, 24 h of treatment increased the mRNA expression of various OB differentiation markers, including Col1 and Spp1 Moreover, Zhao et al.

In addition, PPA treatment for 3 days inhibited RANKL-induced NFATc1, cFos, Mmp9, and Ctsk protein expression. PPA reduced the expression of the second messenger GPRA on the surface of pre-OCs, which increased the level of cAMP inside cells and inhibited the expression of OC-specific genes and OC development The BMP signal transduction pathway regulates OB formation and activation via both conventional Smad-dependent Bmp ligands, receptors, and Smads and non-canonical Smad-independent signaling pathways p38 MAPK pathway A previous study demonstrated that polyphenols promoted OB activation and development via the Smad-dependent signaling pathway 45 , Polyphenols upregulate Bmp2 and activate Smad proteins through a complex serine threonine receptor mechanism that subsequently induces the differentiation of bone marrow stem cells into OBs and modulates the expression of OB-related genes Runx2 , Alpl 45 , The roles of Runx2 include the establishment of the lineage of OBs from multipotent mesenchymal cells, promotion of early OB differentiation, and inhibition of late OB differentiation Runx2 regulates the expression of Sp7 , which is required for OB differentiation and bone formation, by directly binding to the Sp7 promoter 47 , Runx2 is also involved in the OB-selective expression of BSP when interaction occurs between two types of enhancers: a homeodomain protein-binding site the C site and two Runx2-binding sites, R1 and R2 Mmp13 is another example of an OB-specific gene that is influenced by Runx2 75 , Mmp13 is crucial in the bone remodeling process, and a study found that due to the manipulation of the OC lacunar-canalicular network remodeling in the cortical bone, Mmp13 -knockout mice had decreased resistance to fractures in their long bones, indicating that Mmp13 is required for the proper distribution of mineral density in cortical bone Furthermore, Runx2 downregulates the expression of Htra1 by binding to the Htra1 promoter at bp and bp, which subsequently promotes the osteoblastic differentiation of primary mesenchymal progenitor cells Runx2 determines the OB lineage from pluripotent mesenchymal cells, enhances OB differentiation at an early stage, and inhibits OB differentiation at a late stage.

Polyphenols increase the production of calcium, phosphorus, and Col1, which indicates OB mineralization and bone growth Some polyphenols, like 2S,3S -aromadendrinC-β-D-glucopyranoside AG from the extract of U.

wallichiana , can protect the differentiated OBs from serum deprivation-induced apoptosis In addition, polyphenols stimulate OB formation and mineralization through the ER. Estrogen-induced messengers are effectively transmitted in OBs by estrogen receptor alpha ERα Through ER signaling, polyphenols, like kaempferol, induce osteogenic differentiation of cultured OBs, which subsequently increases the transcription of numerous genes of bone differentiation markers Col1 , Runx2 , Bglap , Spp1 , and Sp7 OC precursors differentiate into mature OCs primarily through interactions with two cytokines: M-CSF and RANKL Scalbert A, Manach C, Morand C, Rémésy C, Jiménez L.

Dietary polyphenols and the prevention of diseases. Crit Rev Food Sci Nutr. Weaver CM, Alekel DL, Ward WE, Ronis MJ. Flavonoid intake and bone health. J Nutr Gerontol Geriatr. Austermann K, Baecker N, Stehle P, Heer M. Putative effects of nutritive polyphenols on bone metabolism in vivo -evidence from human studies.

Messina M. A brief historical overview of the past two decades of soy and isoflavone research. J Nutr. Zhang G, Qin L, Shi Y. Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a month randomized, double-blind and placebo-controlled trial.

Huang Z, Cheng C, Wang J, Liu X, Wei H, Han Y, et al. Icariin regulates the osteoblast differentiation and cell proliferation of MC3T3-E1 cells through microRNA by targeting Runt-related transcription factor 2.

Exp Ther Med. Kim B, Lee KY, Park B. Huang J, Yuan L, Wang X, Zhang TL, Wang K. Icaritin and its glycosides enhance osteoblastic, but suppress osteoclastic, differentiation and activity in vitro.

Life Sci. Bodet C, Chandad F, Grenier D. Cranberry components inhibit interleukin-6, interleukin-8, and prostaglandin E production by lipopolysaccharide-activated gingival fibroblasts. Eur J Oral Sci. Yao Z, Xing L, Qin C. Osteoclast precursor interaction with bone matrix induces osteoclast formation directly by an interleukinmediated autocrine mechanism.

Ozaki K, Kawata Y, Amano S, Hanazawa S. Stimulatory effect of curcumin on osteoclast apoptosis. Biochem Pharmacol. Bharti AC, Takada Y, Aggarwal BB. Curcumin diferuloylmethane inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis.

J Immunol. Graef JL, Rendina-Ruedy E, Crockett EK, Ouyang P, Wu L, King JB, et al. Curr Dev Nutr. Smith BJ, Bu SY, Wang Y, Rendina E, Lim YF, Marlow D, et al.

A comparative study of the bone metabolic response to dried plum supplementation and PTH treatment in adult, osteopenic ovariectomized rat. de Vries TJ, El Bakkali I, Kamradt T, Schett G, Jansen IDC, D'Amelio P. What are the peripheral blood determinants for increased osteoclast formation in the various inflammatory diseases associated with bone loss?

Front Immunol. Domazetovic V, Marcucci G, Iantomasi T, Brandi ML, Vincenzini MT. Oxidative stress in bone remodeling: role of antioxidants. Clin Cases Miner Bone Metab. Léotoing L, Wauquier F, Guicheux J, Miot-Noirault E, Wittrant Y, Coxam V.

The polyphenol fisetin protects bone by repressing NF-κB and MKPdependent signaling pathways in osteoclasts. PLoS ONE. Horcajada MN, Offord E. Naturally plant-derived compounds: role in bone anabolism. Curr Mol Pharmacol. Shen CL, Yeh JK, Stoecker BJ, Chyu MC, Wang JS.

Green tea polyphenols mitigate deterioration of bone microarchitecture in middle-aged female rats. Shen CL, Yeh JK, Cao JJ, Wang JS.

Green tea and bone metabolism. Nutr Res. Oka Y, Iwai S, Amano H, Irie Y, Yatomi K, Ryu K, et al. Tea polyphenols inhibit rat osteoclast formation and differentiation.

J Pharmacol Sci. Vester H, Holzer N, Neumaier M, Lilianna S, Nüssler AK, Seeliger C. Green Tea Extract GTE improves differentiation in human osteoblasts during oxidative stress.

J Inflamm. Slatnar A, Jakopic J, Stampar F, Veberic R, Jamnik P. The effect of bioactive compounds on in vitro and in vivo antioxidant activity of different berry juices.

Aqil F, Gupta A, Munagala R, Jeyabalan J, Kausar H, Sharma RJ, et al. Jamun, the Indian Blackberry. Nutr Cancer. Wang H, Cao G, Prior RL. Oxygen radical absorbing capacity of anthocyanins.

J Agric Food Chem. Hubert PA, Lee SG, Lee SK, Chun OK. Dietary polyphenols, berries, and age-related bone loss: a review based on human, animal, and cell studies.

Devareddy L, Hooshmand S, Collins JK, Lucas EA, Chai SC, Arjmandi BH. Blueberry prevents bone loss in ovariectomized rat model of postmenopausal osteoporosis.

J Nutr Biochem. Ehrenkranz JRL, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. Puel C, Quintin A, Mathey J, Obled C, Davicco M, Lebecque P, et al.

Prevention of bone loss by phloridzin, an apple polyphenol, in ovariectomized ratsunder inflammation conditions. Kim JL, Kang MK, Gong JH, Park SH, Han SY, Kang YH. Novel antiosteoclastogenic activity of phloretin antagonizing RANKL-induced osteoclast differentiation of murine macrophages.

Mol Nutr Food Res. Santiago-Mora R, Casado-Díaz A, De Castro MD, Quesada-Gómez JM. Oleuropein enhances osteoblastogenesis and inhibits adipogenesis: the effect on differentiation in stem cells derived from bone marrow.

Osteoporos Int. Chin KY, Ima-Nirwana S. Olives and bone: a green osteoporosis prevention option. Int J Environ Res Public Health. Puel C, Mathey J, Agalias A, Kati-Coulibaly S, Mardon J, Obled C, et al.

Clin Nutr. Sharma S, Anjaneyulu M, Kulkarni SK, Chopra K. Resveratrol, a polyphenolic phytoalexin, attenuates diabetic nephropathy in rats. Kuroyanagi G, Otsuka T, Yamamoto N, Matsushima-Nishiwaki R, Nakakami A, Mizutani J, et al.

Down-regulation by resveratrol of basic fibroblast growth factor-stimulated osteoprotegerin synthesis through suppression of Akt in osteoblasts. Int J Mol Sci. Kondo A, Otsuka T, Kuroyanagi G, Yamamoto N, Matsushima-Nishiwaki R, Mizutani J, et al.

Resveratrol inhibits BMPstimulated VEGF synthesis in osteoblasts: suppression of S6 kinase. Int J Mol Med. Zhao M, Ko SY, Garrett IR, Mundy GR, Gutierrez GE, Edwards JR. The polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1-bone morphogenic protein 2 longevity axis.

Br J Pharmacol. Murgia D, Mauceri R, Campisi G, De Caro V. Advance on resveratrol application in bone regeneration: progress and perspectives for use in oral and maxillofacial surgery. Graef JL, Rendina-Ruedy E, Crockett EK, Ouyang P, King JB, Cichewicz RH, et al.

Select polyphenolic fractions from dried plum enhance osteoblast activity through BMP-2 signaling. Battino M, Bullon P, Wilson M, Newman H. Oxidative injury and inflammatory periodontal diseases: the challenge of anti-oxidants to free radicals and reactive oxygen species.

Crit Rev Oral Biol Med. Brunetti G, Colucci S, Pignataro P, Coricciati M, Mori G, Cirulli N, et al. Several polyphenols have been shown to target Wnt pathway in bone, with evident stimulatory effects of osteoblast differentiation Chen et al.

Accumulation of β-catenin in the cytosol and its nuclear translocation are favored by phenolic compounds, which thus exert stimulatory effects on bone formation. Conversely, polyphenols inhibit bone resorption, through decreasing RANKL expression and relieving SOST inhibitory action on Wnt receptor.

SFRP secreted frizzled-related protein 1, WIF Wnt inhibitory factor 1, CRD cysteine rich domain, CK1 casein kinase 1. Hence, this reduction of SOST does favour the Wnt canonical pathway, involved in osteoblast differentiation Nash et al.

Modulation of Wnt signaling has been reported to be also elicited by EGCG 25 μM, which increases ALP activity through activating β-catenin Mount et al. BMPs are a group of growth factors that belong to the TGF-β superfamily.

Their multiple roles vary from regulation of bone induction, maintenance and repair, to the determination of non-osteogenic embryological developmental processes and to the maintenance of adult tissue homeostasis Chen et al. Involvement of the BMP signaling in polyphenol-mediated bone anabolism has been largely investigated and several evidence show increase of new bone growth through the enhancement of the BMP-2 promoter activity and BMP-2 mRNA and protein expression Zhang et al.

Polyphenols counteract bone disease also through BMP signaling. BMP-2, BMP-6 and BMP-7 are induced by polyphenols to activate the SMAD cascade and, so, to express osteoblastic genes important in osteoblast differentiation and function.

The parallel inhibition of NOGGIN and BMP-3 expression further contributes to these osteoanabolic effects. DLX - 5 distal-less homeobox 5.

EGCG, in particular, has been shown to be a pro-osteogenic agent for the treatment of osteoporosis, thanks to its positive actions on osteoblast functions, on osteogenic differentiation and on mesenchymal stem cell proliferation, through the up-regulation of BMP-2 and Runx2 expression at 5 μM Jin et al.

Hesperidin, the glycoside of hesperetin a flavonone found in citrus fruit , is able to upregulate the expression of mineralization genes, such as OCN and OPN, by both stimulating BMP pathway and down-regulating Noggin signaling, thus also enhancing Runx2 and Osx expression.

Moreover, c-jun and c-fos upregulation and, consequently, AP-1 positive modulation following hesperidin treatment does suggest a possible cross-talk with other signaling pathways, such as Wnt, Hedgehog and MAPKs, implicated in osteoblast differentiation Trzeciakiewicz et al.

Given that the osteoblast lineage is a primary source for VEGF production and that VEGF plays a critical role in coupling of angiogenesis and bone remodeling, it can be postulated that resveratrol increases bone formation also through the regulation of angiogenesis.

Apigenin at 5 and 10 μM positively regulates osteoblast differentiation markers, through upregulating BMP-6 Bandyopadhyay et al. Silibinin can promote osteoblast differentiation through activating BMP signaling and, thus, SMADs phosphorylation and subsequent Runx2 signaling activation.

In response to these osteogenic effects, different osteogenic markers, such as ALP, Col1 and OCN are stimulated Kim et al.

Also isoquercitrin 1 μM has been proved to be involved in osteoblastic differentiation, thanks to its ability to induce BMP-2 and, subsequently, Runx2 and ATF-6 genes to target the OCN gene Wang et al. Resveratrol 1 μM was found to induce osteogenic BMP-2 and to reduce anti-osteogenic BMP-3, thus stimulating osteoblast differentiation and maintaining the phenotype of mature osteoblasts Su et al.

In fact, piceatannol 1 μM increases ALP activity, OCN production and Col1 synthesis, by up-regulating BMP-2 expression both at transcriptional and translational levels, thus improving bone anabolism Chang et al. Caviunin 7- O -[β- d -apiofuranosyl- -β- d -glucopyranoside] CAFG is a non-estrogenic flavonoid glucoside extracted from leaves of Dalbergia sissoo , that has been proved to triggers, in ovariectomized mice fed with 1.

Conversely, quercetin has been shown to negatively modulate TGF-β-induced or BMPinduced SMAD activation Phan et al.

Moreover, although quercetin has been shown to suppress TNF-α Zhang et al. Calcium signal in bone is important in the regulation of osteoclast differentiation, bone resorption and gene transcription. In fact, binding of RANKL to RANK leads to production of inositol trisphosphate IP 3 , that binds to and activates the IP3 receptor IP 3 R , resulting in calcium release from the ER.

In osteoclasts, not only signals from internal stores exist, but also signals derived from calcium entering across the plasma membrane and these cytosolic calcium oscillations are essential for the osteoclastogenesis RANKL-dependent.

The calcium released leads to activation of downstream effector proteins, such as calmodulin kinases and calcineurin. Calcineurin phosphatase dephosphorylates and, thus, activates, NFATc1 that translocates to the nucleus where it initiates the transcription of several osteoclast specific genes, such as cathepsin K, TRAP and calcitonin receptor Hwang and Putney Concerning osteoblasts, studies report a cell sensitivity to high extracellular calcium concentrations, in that they may affect the proliferation and differentiation of osteoblasts Farley et al.

Polyphenols like resveratrol have been shown to regulate different cellular processes, by acting as ligand for transmembrane proteins, like voltage-gated calcium channels and plasma membrane calcium ATPase Sareen et al.

The protective actions of polyphenols on bone metabolism via modulating the calcium signaling are mainly achieved through repression of bone resorption, with osteoclastogenic genes as primary targets Yamaguchi and Sugimoto ; Wu et al.

One of the main properties characterizing polyphenols and, as such, the most extensively studied, is represented by their ability to exert anti-inflammatory actions by negatively regulating the inflammation pathway and, especially, its crucial NF-κB TF.

Because NF-κB gives rise to signals implicated in varied transcriptional programs with broad physiological and medical effects such as immunological response, development Hayden and Ghosh ; Oeckinghaus and Ghosh , survival, apoptosis and cell growth Guttridge et al.

In fact, cooperative interactions with other TFs or receptor molecules are responsible for integration of NF-κB functions with other cell-signaling pathways, thanks to different specific binding sites in the molecule itself, or on the promoters of the target genes Perkins The estrogen receptor, in fact, may interact via protein—protein interactions with NF-κB, resulting in modulation of the binding of NF-κB to NF-κB response elements, thus regulating NF-κB-dependent gene transcription in a cell-type-specific manner and has important implications in the inflammatory processes.

For example, estrogen downregulates IL-6 production indirectly, by binding to NF-κB and thus reducing the IL-6 promoter activity Stein and Yang In this field, NF-κB is also investigated in oncogenesis, because of its ability to regulate genes involved in proliferation and apoptosis processes, with elevation of its levels in some types of cancers Sovak et al.

In view of this, estrogen has been shown to inhibit different tumorigenic cell line growth, by binding to NF-κB Pratt et al.

Inflammation is also linked to the development of different chronic diseases, from heart diseases, to obesity, diabetes and osteoporosis, and, furthermore, given that osteoblasts and adipocytes derive from the same MSC compartment, polyphenol action on switching differentiation towards osteoblastogenesis, rather than adipogenesis, makes these molecules a promising tool to treat metabolic dysfunctions Ginaldi and De Martinis Negative regulation of NF-κB by Wnt signal is also achieved through the physical interaction between β-catenin and NF-κB, that results in a minor DNA binding activity and, thus, in diminished NF-κB-related gene expression.

Given the ability of Wnt signaling to stimulate or suppress NF-κB pathway, opposite properties of anti-inflammation and pro-inflammation are of evidence, even if most of the results show a prevalence of the anti-inflammatory actions Ma and Hottiger In the subsequent developmental stages, a synergism can be observed, when the signals begin to function cooperatively Itasaki and Hoppler However, an increment of the Wnt signal could lead to cancer initiation and progression, being β-catenin involved in carcinogenesis, especially in colorectal cancer.

If it is true that many beneficial actions of polyphenols on bone metabolism are also achieved by enhancement of the Wnt signaling, it is also true that some polyphenol effects on cancer prevention are achieved by negatively targeting Wnt signaling Amado et al.

These opposite effects could be explained by the different types of polyphenols involved and, most importantly, by the doses. By taking these observations into account, it is clear that the present understanding of how phytochemicals act on a specific biological system is still far from an effective and reproducible application in vivo.

This consideration is also supported by the observation that some polyphenols differ from others in terms of bioavailability and bioactivity.

Despite their structure diversity, they share common different properties, which are responsible for the even more growing interest in researchers and society. These multiple features, which include anti-inflammation, anti-oxidation and anti-aging, contribute to the prevention of human diseases and, specifically for the above analyzed bone system context, to the protection against bone diseases, in so far as they also include anti-resorption and pro-osteogenesis.

The many different possible chemical structures are also made more complex by the binding of sugars, such as glucose, galactose, rhamnose, xylose, rutinose, arabinopyranose and arabinofuranose to form more stable glycosylated derivatives to be stored in vacuoles and chloroplasts and by esterification with lipids and organic acids.

Hence, these aspects represent an important key point that determines the degree of polyphenol bioavailability and absorption: in fact, in the small intestine, enzymes such as glycosylases are able to metabolize the glycosylated forms to aglycones, while only specific strains of the gut microbiota in the colon, are able to break the esterification bond and to generate active metabolites Marín et al.

Besides polyphenol metabolism, other aspects to be considered are the subsequent modifications carried out by enterocytes, such as methylation, sulfation and glucuronidation, representing a detoxification mechanism by which the organism prepares the molecule to be excreted.

Before polyphenols are taken to tissues or excreted through bile, urine or faeces, conjugation, mainly in the liver, with other carrier molecules or interaction with other types of polyphenols is also possible, thus increasing the factors to take into account when considering polyphenol bioavailability.

For example, by targeting the gut bacteria genome with mutagenesis techniques to generate new and improved strains, could allow them to be more efficient in metabolizing polyphenols or to produce new or more active metabolites, while increasing the lipophilicity by combination of polyphenols with other molecules and the addiction of lipophilic groups reduces the hydrogen bonding potential.

In this field, phytosomes with unique vehicle properties that arise from the complexation of a phospholipid with a phytochemical, exhibit better pharmacokinetic and pharmacodynamic profiles than free phytochemical compounds Jain et al. Another way to improve bioavailability, involves structural changes aimed at increasing the plasma half-life clearance of compounds, the involvement of a vector molecule, which is directly conjugated with the polyphenol and which has affinity for a relative receptor on the target tissue, or the development of micro or nano-carriers such as microspheres, nanoparticles, microemultions and so on Khushnud and Mousa Regarding the engineering of delivery systems and devices, nanotechnologies, which are getting researchers more and more interested in, could represent a promising approach, as they involve the tailoring of materials at atomic level, in view of obtaining unique properties suitable for a wide variety of applications Gleiter Nanomedicine is a new field of treatments based on nanosystems able to enhance drugs delivery, drugs specific targeting and drugs half-life, thanks to their properties of passive accumulation in specific tissues, stability, specificity and biocompatibility.

So, given the relative high clearance of polyphenols and their low stability, a nanotechnological approach aimed at increasing the phytochemical circulation in the bloodstream could represent a way to be investigated Tabrez and Priyadarshini Furthermore, nanotechnologies specificity could be improved by creating targeted nanoparticle systems, particularly useful when the phytochemical delivery is to be obtained via topical or parenteral delivery, rather than by the classical enteral delivery.

For example, considering the transdermal administration of a drug, its penetration often finds difficulties due to skin anatomy, with different routes of penetration; so, the employ of nanoparticles provide a number of advantages, including increased xenobiotic solubility and, thus, permeation, reduced toxicity, as the first-pass hepatic metabolism is avoided and high affinity for cellular membranes, due to nanoparticles surface properties Uchechi et al.

In the past few decades, accumulating data have shown potential beneficial effects of polyphenols on human health. In particular, thanks to their multiple beneficial properties, which can modulate different signaling pathways, polyphenols are able to target the diverse bone cellular compartments, thus exerting a noticeable bone protection Đudarić et al.

However, despite these findings, care must be taken when considering dietary intake of polyphenols, because they can act in a double manner, being dependent on many other associated factors, such as bioavailability, diet or dosage Martin and, therefore, the need to develop tests aimed at establishing the right dose to ensure safety and the low risk of adverse effects is even more crucial.

Furthermore, besides dosage, also the form of the phenolic compound is of note, in fact it influences its bioavailability, together with the presence of intestinal microflora and gut enzymes. So, biomedical applications of these natural compounds are severely hindered by their low bioavailability, rapid metabolism, and often by unfavorable physico-chemical properties, e.

a generally low water solubility, as well as still insufficient scientific data derived from preclinical and clinical studies. The main purpose of the standards concerning production, distribution and intended use of medicinal products, is to ensure the protection of public health and to enable the competent authorities to make decisions on the basis of uniform tests and by reference to uniform criteria, by contributing to prevent differences of view.

Not less important, they have not yet been shown to represent a definitive cure for bone diseases. Aiming at reducing the differences by setting them against the evolution of science, it is concluded that properties and intended use of medicinal products are diversified not only on the basis of already existing scientific data, but also by the appropriate understanding of the existing legislation.

Therefore, thanks to their beneficial osteoanabolic effects, polyphenols could be used as adjuvants in the prevention, treatment and mitigation of the osteoporotic disease, with a strict control of the dosages at which their health benefits and lack of adverse effects have been shown.

Consequently, more in vivo tests should be necessary to determine, at first, which types of intervention on molecules do improve their bioavailability, then which doses are better useful to get the desired effects, by also taking into account the toxicity aspect.

Furthermore, in a medical devices context, it is important to evaluate how polyphenols combined with medical devices do act and eventually modify their properties in the different pathways, following a sterilization process, for example, or the all necessary steps aimed at ensuring an excellent result of quality control also in the post marketing activity.

Aiman Saleh A. Muhammad Azeem, Muhammad Hanif, … Usman Abid. Caviunin 7- O -[β- d -apiofuranosyl- -β- d -glucopyranoside]. Abbas AK, Lichtman AH, Pillai S Basic immunology: functions and disorders of the immune system.

Saunders, Philadelphia. Adlercreutz H Phyto-oestrogens and cancer. Lancet Oncol — Article PubMed Google Scholar. Adlercreutz H, Heinonen S Phytoestrogens, cancer and coronary heart disease.

BioFactors — Article CAS PubMed Google Scholar. Aggarwal BB Activation of transcription factor NF-kappaB is suppressed by curcumin diferuloylmethane. J Biol Chem — doi: Al-Obaidi MMJ, Al-Bayaty FH, Al Batran R et al a Protective effect of ellagic acid on healing alveolar bone after tooth extraction in rat—a histological and immunohistochemical study.

Arch Oral Biol — Al-Obaidi MMJ, Al-Bayaty FH, Al Batran R, Hussaini J, Khor GH et al b Impact of ellagic acid in bone formation after tooth extraction: an experimental study on diabetic rats. Sci World J. Google Scholar. Life Sci — Anderson JJ, Ambrose WW, Garner SC Biphasic effects of genistein on bone tissue in the ovariectomized, lactating rat model.

Proc Soc Exp Biol Med — Ang ESM, Pavlos NJ, Chai LY et al Caffeic acid phenethyl ester, an active component of honeybee propolis attenuates osteoclastogenesis and bone resorption via the suppression of RANKL-induced NF-kappaB and NFAT activity.

J Cell Physiol — Ang ESM, Yang X, Chen H et al Naringin abrogates osteoclastogenesis and bone resorption via the inhibition of RANKL-induced NF-κB and ERK activation. FEBS Lett — Arts J, Kuiper GG Differential expression of extrogen receptors alfa and beta mRNA during differentiation of human osteoblast SV-HFO cells.

Endocr Soc — Article CAS Google Scholar. Bäckesjö C-M, Li Y, Lindgren U, Haldosén L-A Activation of sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. J Bone Miner Res — Article Google Scholar. Bandyopadhyay S, Lion JM, Mentaverri R et al Attenuation of osteoclastogenesis and osteoclast function by apigenin.

Biochem Pharmacol — Baur JA, Pearson KJ, Price NL et al Resveratrol improves health and survival of mice on a high-calorie diet. Nature — Article CAS PubMed PubMed Central Google Scholar.

Bertelli AAE, Migliori M, Panichi V et al Oxidative stress and inflammatory reaction modulation by white wine. Ann NY Acad Sci — Bhargavan B, Gautam AK, Singh D et al Methoxylated isoflavones, cajanin and isoformononetin, have non-estrogenic bone forming effect via differential mitogen activated protein kinase MAPK signaling.

J Cell Biochem — Bharti A, Donato N Curcumin diferuloylmethane down-regulates the constitutive activation of nuclear factor—κB and IκBα kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis.

Blood — Bharti AC, Takada Y, Aggarwal BB Curcumin diferuloylmethane inhibits receptor activator of NF-κB ligand-induced NF-κB activation in osteoclast precursors and suppresses osteoclastogenesis.

J Immunol — Björnström L, Sjöberg M Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol — Article PubMed CAS Google Scholar. Bodet C, Chandad F, Grenier D Cranberry components inhibit interleukin-6, interleukin-8, and prostaglandin E production by lipopolysaccharide-activated gingival fibroblasts.

Eur J Oral Sci — Boissy P, Andersen TL, Abdallah BM et al Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res — Bonewald LF The amazing osteocyte.

Braun KF, Ehnert S, Freude T et al Quercetin protects primary human osteoblasts exposed to cigarette smoke through activation of the antioxidative enzymes HO-1 and SOD Sci World J — Bu SY, Lerner M, Stoecker BJ et al Dried plum polyphenols inhibit osteoclastogenesis by downregulating NFATc1 and inflammatory mediators.

Calcif Tissue Int — Bu SY, Hunt TS, Smith BJ Dried plum polyphenols attenuate the detrimental effects of TNF-α on osteoblast function coincident with up-regulation of Runx2, Osterix and IGF-I.

J Nutr Biochem — Buluc M, Demirel-Yilmaz E Resveratrol decreases calcium sensitivity of vascular smooth muscle and enhances cytosolic calcium increase in endothelium. Vasc Pharmacol — Callaway DA, Jiang JX Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases.

J Bone Miner Metab. PubMed Google Scholar. Casanova M, You L, Gaido KW et al Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors α and β in vitro. Toxicol Sci — Casarin RC, Casati MZ, Pimentel SP et al Resveratrol improves bone repair by modulation of bone morphogenetic proteins and osteopontin gene expression in rats.

Int J Oral Maxillofac Surg — Cauley J Estrogen and bone health in men and women. Steroids — Chan WH, Wu HY, Chang WH Dosage effects of curcumin on cell death types in a human osteoblast cell line.

Food Chem Toxicol — Chang J, Jeong H Discovery of novel drug targets and their functions using phenotypic screening of natural products. J Ind Microbiol Biotechnol — Chang JK, Hsu YL, Teng IC, Kuo PL Piceatannol stimulates osteoblast differentiation that may be mediated by increased bone morphogenetic protein-2 production.

Eur J Pharmacol —9. Chen J-R, Lazarenko OP Diet-derived phenolic acids regulate osteoblast and adipocyte lineage commitment and differentiation in young mice.

Chen XW, Garner SC, Anderson JJB Isoflavones regulate interleukin-6 and osteoprotegerin synthesis during osteoblast cell differentiation via an estrogen-receptor-dependent pathway. Biochem Biophys Res Commun — Chen X, Garner SC, Quarles LD, Anderson JJB Effects of genistein on expression of bone markers during MC3T3-E1 osteoblastic cell differentiation.

Chen D, Zhao M, Mundy GR Bone morphogenetic proteins. Growth Factors — Chen KM, Ge BF, Liu XY et al Icariin inhibits the osteoclast formation induced by RANKL and macrophage-colony stimulating factor in mouse bone marrow culture.

Pharmazie — CAS PubMed Google Scholar. Chen F, Wang H, Xiang X et al a Curcumin increased the differentiation rate of neurons in neural stem cells via wnt signaling in vitro study. J Surg Res — Chen X, Li Y, Lin Q et al b Tea polyphenols induced apoptosis of breast cancer cells by suppressing the expression of Survivin.

Sci Rep Article PubMed PubMed Central CAS Google Scholar. Chen Z, Xue J, Shen T et al Curcumin alleviates glucocorticoid-induced osteoporosis by protecting osteoblasts from apoptosis in vivo and in vitro.

Clin Exp Pharmacol Physiol — Choi EM Protective effect of quercitrin against hydrogen peroxide-induced dysfunction in osteoblastic MC3T3-E1 cells. Exp Toxicol Pathol — Biol Pharm Bull — Choi EM, Suh KS, Kim YS et al Soybean ethanol extract increases the function of osteoblastic MC3T3-E1 cells. Phytochemistry — Choi SW, Son YJ, Yun JM, Kim SH Fisetin inhibits osteoclast differentiation via downregulation of p38 and c-Fos-NFATc1 signaling pathways.

Evidence Based Complement Altern Med. Chowdhury TT, Salter DM, Bader DL, Lee DA Signal transduction pathways involving p38 MAPK, JNK, NFkB and AP-1 influences the response of chondrocytes cultured in agarose constructs to IL-1β and dynamic compression.

Inflamm Res — Comalada M, Ballester I, Bailón E et al Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure-activity relationship.

Confavreux CB, Levine RL, Karsenty G A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms. Mol Cell Endocrinol — Cos P, Apers S Phytoestrogens: recent developments.

Planta Med — Crasto GJ, Kartner N, Yao Y et al Luteolin inhibition of V-ATPase a3-d2 interaction decreases osteoclast resorptive activity. Crozier A, Jaganath IB, Clifford MN Dietary phenolics: chemistry, bioavailability and effects on health.

Nat Prod Rep — Csaki C, Mobasheri A, Shakibaei M Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL-1beta-induced NF-kappaB-mediated inflammation and apoptosis.

Arthritis Res Ther R Cui L, Jia X, Zhou Q et al Curcumin affects beta-catenin pathway in hepatic stellate cell in vitro and in vivo. J Pharm Pharmacol — Ann Ist Super Sanita — Phytomedicine — Int J Biol Sci — De Stefano D, Maiuri MC, Simeon V et al Lycopene, quercetin and tyrosol prevent macrophage activation induced by gliadin and IFN-γ.

Eur J Pharmacol — De Wilde A, Lieberherr M, Colin C, Pointillart A A low dose of daidzein acts as an ERbeta-selective agonist in trabecular osteoblasts of young female piglets. Die L, Yan P, Jun Jiang Z et al Glycogen synthase kinase-3 beta inhibitor suppresses Porphyromonas gingivalis lipopolysaccharide-induced CD40 expression by inhibiting nuclear factor-kappa B activation in mouse osteoblasts.

Mol Immunol — Dobrydneva Y, Williams RL, Blackmore PF trans-Resveratrol inhibits calcium influx in thrombin-stimulated human platelets. Br J Pharmacol — Dobrydneva Y, Williams RL, Blackmore PF Diethylstilbestrol and other nonsteroidal estrogens: novel class of store-operated calcium channel modulators.

J Cardiovasc Pharmacol — Dragan S, Andrica F, Serban M-C, Timar R Polyphenols-rich natural products for treatment of diabetes. Curr Med Chem — Đudarić L, Fužinac-Smojver A, Muhvić D, Giacometti J The role of polyphenols on bone metabolism in osteoporosis. Food Res Int — Ebrahimi A, Schluesener H Natural polyphenols against neurodegenerative disorders: potentials and pitfalls.

Ageing Res Rev — Off J Eur Communities L — Eklou-Kalonji E, Denis I, Lieberherr M, Pointillart A Effects of extracellular calcium on the proliferation and differentiation of porcine osteoblasts in vitro.

Cell Tissue Res — Farha MA, Brown ED Strategies for target identification of antimicrobial natural products. Nat Prod Rep. Farley JR, Hall SL, Tanner MA, Wergedal JE Specific activity of skeletal alkaline phosphatase in human osteoblast-line cells regulated by phosphate, phosphate esters, and phosphate analogs and release of alkaline phosphatase activity inversely regulated by calcium.

Feng J, Liu S, Ma S et al Protective effects of resveratrol on postmenopausal osteoporosis: regulation of SIRT1-NF-kB signaling pathway. Acta Biochim Biophys Sin — Folwarczna J, Zych M, Burczyk J et al Effects of natural phenolic acids on the skeletal system of ovariectomized rats.

Folwarczna J, Pytlik M, Zych M et al Effects of caffeic and chlorogenic acids on the rat skeletal system. Eur Rev Med Pharmacol Sci — Gao YH, Yamaguchi M a Inhibitory effect of genistein on osteoclast-like cell formation in mouse marrow cultures.

PLoS ONE 8:e Ge C, Xiao G, Jiang D, Franceschi RT Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J Cell Biol — Ghibelli L, Cerella C, Diederich M The dual role of calcium as messenger and stressor in cell damage, death, and survival.

Int J Cell Biol. Ginaldi L, De Martinis M Osteoimmunology and beyond. Curr Med Chem. PubMed PubMed Central Google Scholar. Gleiter H Nanostructured materials: basic concepts and microstructure.

Acta Mater — Gómez-Florit M, Monjo M, Ramis JM Identification of quercitrin as potential therapeutic agent for periodontal applications.

J Periodontol — Gómez-Florit M, Monjo M, Ramis JM Quercitrin for periodontal regeneration: effects on human gingival fibroblasts and mesenchymal stem cells. Sci Rep. González-Gallego J, García-Mediavilla MV, Sánchez-Campos S, Tuñón MJ Fruit polyphenols, immunity and inflammation.

Br J Nutr Suppl :S15—S Cytogenet Cell Genet — Goto T, Hagiwara K, Shirai N et al Apigenin inhibits osteoblastogenesis and osteoclastogenesis and prevents bone loss in ovariectomized mice.

Cytotechnology — Grigoriadis AE, Wang Z, Cecchini MG et al c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling.

Science — Gruber R, Graninger W, Bobacz K et al BMPinduced osteogenic differentiation of mesenchymal cell lines is not modulated by sex steroids and resveratrol. Cytokine — Gu Q, Cai Y, Huang C et al Curcumin increases rat mesenchymal stem cell osteoblast differentiation but inhibits adipocyte differentiation.

Pharmacogn Mag — Guicheux J, Lemonnier J, Ghayor C et al Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation.

Guimarães MR, Coimbra LS, De Aquino SG et al Potent anti-inflammatory effects of systemically administered curcumin modulate periodontal disease in vivo. J Periodontal Res — Guimarães MR, de Aquino SG, Coimbra LS et al Curcumin modulates the immune response associated with LPS-induced periodontal disease in rats.

Innate Immun — Guntur AR, Rosen CJ The skeleton: a multi-functional complex organ. New insights into osteoblasts and their role in bone formation: the central role of PI3Kinase. J Endocrinol — Guo AJ, Choi RC, Zheng KY et al a Kaempferol as a flavonoid induces osteoblastic differentiation via estrogen receptor signaling.

Chin Med J Biol Chem