Quercetin as an Agent for Protecting the Bone: A Review of the Current Evidence
Abstract
:1. Introduction
2. In Vivo Evidence on the Effects of Quercetin on Bone
3. In Vitro Evidence of the Effects of Quercetin on Bone Cells
3.1. The Effects of Quercetin on Osteoblastogenesis
3.2. The Effects of Quercetin on Osteoclastogenesis
4. The Underlying Mechanisms of Action of Quercetin as a Bone-Protecting Agent
4.1. Regulation of the Receptor Activator of Nuclear Factor-Kappa B (RANK)/RANKL/Osteoprotegerin System
4.2. Regulation of MAPK Signalling
4.3. Regulation of Apoptosis
4.4. Antioxidative Effects
4.5. Anti-Inflammatory Effects
4.6. Canonical Wnt/β-Catenin Signalling
4.7. BMP and TGF-β Signalling
4.8. Regulation of Angiogenesis
5. Perspectives
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
8-OHdG | 8-hydroxy-2′-deoxyguanosine |
ACP | Acid phosphatase |
Akt | Protein kinase B |
ALP | Alkaline phosphatase |
ANG-1 | Angiogenin-1 |
AP-1 | Activator protein-1 |
Apaf-1 | Apoptotic protease activating factor-1 |
APC | Adenomatosis polyposis coli |
ARE | Antioxidant responsive element |
Arg-1 | Arginase-1 |
ATF6 | Activating transcription factor 6 |
Axin | Axis inhibition protein 2 |
Bak | Bcl-2 homologous antagonist/killer |
Bax | Bcl-2-associated X protein |
Bcl-2 | B-cell lymphoma 2 |
Bcl-XL | B-cell lymphoma-extra large |
bFGF | Basic fibroblast growth factor |
BFR | Bone formation rate |
BMD | Bone mineral density |
BMP-2 | Bone morphogenetic protein-2 |
B.Pm | Bone perimeter |
BS | Bone surface |
BSP | Bone sialoprotein |
BV | Bone volume |
CalcR | Calcitonin receptor |
CAT | Catalase |
Cbα1 | Core binding factor alpha 1 |
c-Fos | Cellular proto-oncogene |
CHOP | CCAAT/enhancer-binding protein homologous protein |
CK1α | Casein kinase 1 alpha |
COL1 | Type 1 collagen |
Conn.D | Connectivity density |
Cr.Ar | Cortical bone area |
Cr.Th | Cortical thickness |
CRP | C-reactive protein |
CTSK | Cathepsin K |
CTX | C-terminal telopeptide of type 1 collagen |
dATP | Deoxyadenosine triphosphate |
Dc-Stamp | Dendritic cell-specific transmembrane protein |
DISC | Death-inducing signalling complex |
DKK1 | Dickkopf-related protein 1 |
DNA | Deoxyribonucleic acid |
E.Pm | Endosteal perimeter |
ERK | Extracellular signal-regulated kinase |
Ets1 | Ets oncogene homolog 1 |
FADD | Fas-associated death domain |
FasL | Fas ligand |
GCLC | γ-glutamyl-cysteine ligase catalytic subunit |
GPx | Glutathione peroxidase |
GRP78 | Glucose-regulated protein |
GSH | Reduced glutathione |
GSK3β | Glycogen synthase kinase-3 beta |
GST | Glutathione-S-transferase |
H2O | Water molecule |
H2O2 | Hydrogen peroxide |
H+ ATPase | Vacuolar type proton ATPase |
HO-1 | Heme-oxygenase 1 |
HUVECs | Human umbilical vein endothelial cells |
IL-1β | Interleukin-1 beta |
IL-6 | Interleukin-6 |
IL-10 | Interleukin-10 |
i.m. | Intramuscular |
iNOS | Inducible nitric oxide synthase |
i.p. | Intraperitoneal |
IRE1 | Inositol-requiring enzyme 1 |
JNK | c-Jun N-terminal kinase |
Keap1 | Kelch-like ECH-associated protein 1 |
LDH | Lactate dehydrogenase |
LPS | Lipopolysaccharides |
LRP5/6 | Low-density lipoprotein receptor-related protein 5/6 |
Maf | Musculoaponeurotic fibrosarcoma oncogene homolog |
MAP2K | Mitogen-activated protein kinase kinase |
MAP3K | Mitogen-activated protein kinase kinase kinase |
MAPK | Mitogen-activated protein kinase |
MAR | Mineral apposition rate |
M-CSF | Macrophage colony-stimulating factor |
MDA | Malondialdehyde |
MMP-9 | Matrix metalloproteinase-9 |
MS | Mineralising surface |
MSCs | Mesenchymal stem cells |
N2O3 | Dinitrogen trioxide |
NFATc1 | Nuclear factor of activated T-cells cytoplasmic 1 |
NF-κB | Nuclear factor-kappa B |
NO• | Nitric oxide |
NO2• | Nitrogen dioxide |
NQO1 | Nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 |
Nrf2 | Nuclear factor erythroid 2-related factor-2 |
O2 | Oxygen molecule |
O2•− | Superoxide anions |
OH• | Hydroxyl radicals |
ONOO- | Peroxynitrite anion |
P1NP | N-terminal propeptide of type 1 procollagen |
PARP | Poly(ADP-ribose) polymerase |
PBMCs | Peripheral-blood monocytic cells |
PERK | Protein kinase RNA-like endoplasmic reticulum kinase |
Prdx5 | Peroxiredoxin-5 |
PTH | Parathyroid hormone |
RANK | Receptor activator of nuclear factor-kappa B |
RANKL | Receptor activator of nuclear factor-kappa B ligand |
RNS | Reactive nitrogen species |
ROS | Reactive oxygen species |
Runx-2 | Runt-related transcription factor 2 |
s.c. | Subcutaneous |
SMAD | Suppressor of mothers against decapentaplegic |
SMI | Structure model index |
SMURF1 | Suppressor of mothers against decapentaplegic ubiquitylation regulatory factor 1 |
SOD | Superoxide dismutase |
SOST | Sclerostin |
STZ | Streptozotocin |
T.Ar | Periosteal area |
Tb.N | Trabecular number |
Tb.Pf | Trabecular pattern factor |
Tb.Sp | Trabecular separation |
Tb.Th | Trabecular thickness |
TFSP | Tibia–fibula separating point |
TGF-β | Transforming growth factor-beta |
TNF-α | Tumour necrosis factor-alpha |
T.Pm | Periosteal perimeter |
TRAF6 | Tumour necrosis factor receptor-associated factor 6 |
TRAIL | Tumour necrosis factor-related apoptosis-inducing ligand |
TRAP | Tartrate-resistant acid phosphatase |
TV | Total volume |
VEGF | Vascular endothelial growth factor |
Wnt | Wingless |
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Type of Animal | Type of Induction | Intervention (Dose, Route and Duration) | Research Findings | References |
---|---|---|---|---|
Female Sprague–Dawley rats | Bilateral ovariectomy | Quercetin (50 mg/kg/day, oral)—8 weeks | Bone mineral density (BMD): ↑; elastic radial degree: ↑; maximum radial degree: ↑; elastic load: ↑; maximum load: ↑; Tb.N: ↑; Tb.Th: ↑ | [29] |
Female albino rats | Bilateral ovariectomy | Quercetin (50 mg/kg/day, oral)—30 days | ACP: ↓; ALP: ↓; calcium: ↑; phosphorus: ↑; TNF-α: ↓; MDA: ↓; GSH: ↑ | [30] |
Quercetin-loaded phytosome nanoparticles (10 or 50 mg/kg, oral)—30 days | ||||
Female C57BL/6J mice | Bilateral ovariectomy | Quercetin (2.5% diet)—4 weeks | Plasma calcium & phosphate: ↔; BMD (total lumbar & total femur): ↑; Cr.Ar: ↑; Cr.Th: ↑; section modulus (rectangular & polar): ↑; BV/TV: ↑; Tb.Th: ↑; Tb.N: ↑; Tb.Sp: ↓; osteoid volume: ↑; osteoid surface: ↑ | [31] |
Adult female rats | Bilateral ovariectomy | Quercetin (5 mg/kg/day, oral)—12 weeks | BMD (femur epiphysis & proximal tibia): ↑; BV/TV: ↑; Tb.Th: ↔; Tb.Sp: ↓; Tb.N: ↑; femur (Cr.Ar & T.Ar): ↑; tibia (T.Ar, B.Pm & E.Pm): ↑; maximum power: ↔; energy: ↔; stiffness: ↔; osteocalcin: ↓; CTX: ↓ | [32] |
Quercetin-6-C-β-d-glucopyranoside (5 mg/kg/day, oral)—12 weeks | BMD (femur epiphysis, proximal tibia, L4, femur diaphysis & TFSP): ↑; BV/TV, Tb.Th & Tb.N (femur diaphysis & proximal tibia): ↑; Tb.Sp (femur diaphysis & proximal tibia): ↓; Cr.Ar, Cr.Th, T.Ar, T.Pm, B.Pm & E.Pm (femur & tibia): ↑; maximum power: ↑; energy: ↑; stiffness: ↑; osteocalcin: ↓; CTX: ↓ | |||
Growing female rats | - | Quercetin-6-C-β-d-glucopyranoside (5 or 10 mg/kg/day, oral)—12 weeks | MAR: ↑; BFR: ↑; BMD (femur & tibia): ↑; Cr.Ar, Cr.Th, T.Ar, T.Pm, B.Pm & E.Pm (mid-diaphysis & TFSP): ↑ | [33] |
Adult female rats | Bilateral ovariectomy | Quercetin-6-C-β-d-glucopyranoside (5 mg/kg/day, oral)—12 weeks | MAR & BFR (femur diaphysis): ↑; BV/TV, Tb.N, Tb.Th & Conn.D (femur epiphysis): ↑; Tb.Sp, Tb.Pf & SMI (femur epiphysis & proximal tibia): ↓; BV/TV, Tb.N & Conn.D (proximal tibia): ↑ | |
Female Sprague–Dawley rats | Bilateral ovariectomy + femoral bone defect (size: 3.5 × 4 mm) | Hydroxyapatite bioceramic microspheres loaded with quercetin (200 mM)—8 weeks | BMD: ↑; Tb.Th: ↑; vessel: ↑ | [34] |
Aged, retired breeder Fischer 344 rats | Bilateral ovariectomy | Quercetin (1000 mg/kg diet) + vitamin D3 (2400 IU/kg diet) + genistein (500 mg/kg diet) + resveratrol (200 mg/kg diet)—4 weeks | BMD (whole femur, diaphysis & metaphysis): ↔; BMD (lumbar, L4 & L5): ↔; BV/TV: ↔; BS/BV: ↔; Tb.N: ↔; Tb.Sp: ↔; Tb.Th: ↔; degree of anisotropy: ↔; Conn.D: ↔; osteoclast number: ↔; cortical BV/TV: ↔; Cr.Th: ↔; adipocyte number: ↓ | [35] |
Quercetin (2000 mg/kg diet) + vitamin D3 (2400 IU/kg diet) + genistein (1000 mg/kg diet) + resveratrol (400 mg/kg diet)—4 weeks | ||||
Female Sprague–Dawley rats | Bilateral ovariectomy | Quercitrin (50, 100 or 200 mg/kg/day, oral)—60 days | BMD (distal femur): ↑; maximum energy absorption, maximum fracture load & stiffness (femoral neck): ↑; calcium: ↑; phosphorus: ↑; ALP: ↑; P1NP: ↑; CTX: ↓; TRAP: ↓; osterix: ↑; Runx-2: ↑ | [36] |
Female Wistar albino rats | Bilateral ovariectomy | Isoquercitrin (60 mg/kg/day, oral)—8 weeks | Lumbar compression strength: ↑; calcium & phosphorus (serum): ↔; calcium, phosphorus & creatinine (urine): ↓; ALP: ↓; osteocalcin: ↓; VEGF: ↑; β-catenin: ↑; NF-κB: ↓ | [37] |
Male Wistar albino rats | STZ (50 mg/kg, i.p.) | Quercetin (15 mg/kg/day, i.p.)—4 weeks | Plasma calcium & magnesium: ↑; BV/TV: ↑; Tb.N: ↑; Tb.Th: ↑; load: ↑ | [38] |
Male Sprague–Dawley rats | STZ (100 mg/kg, i.p.) | Quercetin (30 or 50 mg/kg, oral)—8 weeks | ALP: ↑; osteocalcin: ↑; urinary deoxypyridinoline: ↑; load: ↑; stiffness: ↑; energy absorption: ↑; Young’s modulus: ↑; BMD: ↑; Tb.N: ↑; Tb.Th: ↑; Tb.Sp: ↓; BV/TV: ↑; SMI: ↓; Conn.D: ↑; Cr.Th: ↑; Cr.Ar: ↑; BFR: ↑; MAR: ↑; MS: ↑; 8-OHdG: ↓; total antioxidant capacity: ↑; SOD: ↑; GPx: ↑; CAT: ↑; GST: ↑ | [39] |
Female Sprague–Dawley rats | Methylprednisolone sodium succinate (40 mg/kg, s.c.) | Quercetin (150 mg/kg, thrice a week, oral)—6 weeks | Bone strength: ↑; osteocalcin: ↑; CTX: ↔; calcium: ↔; phosphorus: ↔; Tb.Th: ↑; Cr.Th: ↑; osteoblast number: ↑; moment of inertia: ↑ | [40] |
Female Wistar rats | Glucocorticoid methyl prednisolone (40 mg/kg, s.c.) | Quercetin-loaded transfersome film (10 mg/kg/day, topical)—15 days | Calcium: ↑; phosphorus: ↑; ALP: ↓; TRAP: ↓; femur weight: ↑; femur density: ↑; tensile strength: ↑ | [41] |
Female Sprague–Dawley rats | Bile-duct ligation | Quercetin (150 μmol/kg/day, injection)—4 weeks | osteocalcin: ↑; CTX: ↔; calcium: ↔; phosphorus: ↔; bone strength: ↑; Tb.Th: ↑; Cr.Th: ↑; Cr.Ar: ↑; osteoclast number: ↓; osteoblast number: ↑ | [42] |
Female fertile Y59 rats | Retinoic acid (80 mg/kg/day, oral) | Quercetin (100 mg/kg/day, oral)—14 days | BMD: ↑; ash, calcium and phosphorus content (femur): ↑; femur weight: ↑; femur length: ↑; MDA: ↓; GSH: ↑ | [43] |
- | Quercetin (100 mg/kg/day, oral)—14 days | Ash, calcium and phosphorus content (femur): ↔; femur weight: ↔; femur length: ↔; MDA: ↔; GSH: ↔ | ||
Male Wistar albino rats | Zinc oxide nanoparticles (600 mg/kg/day, 5 days) | Quercetin (200 mg/kg/day, oral)—3 weeks | Bone ALP: ↑; CTX: ↓; calcium: ↔; phosphorus: ↔; magnesium: ↔; NO•: ↓; DNA damage: ↓; TNF-α: ↑; IL-6: ↓; CRP: ↓ | [44] |
Male BALB/c mice | Titanium-particle-mediated osteolysis | Quercetin (50 or 100 mg/kg, oral)—13 days | Osteolysis: ↓; bone area: ↑; osteoclast number: ↓; PERK: ↓; IRE1: ↓; GRP78: ↓; CHOP: ↓; cleaved caspase-12: ↓; cleaved caspase-3: ↓; Bcl-2: ↑ | [45] |
Female C57BL/6 mice | Titanium-particle-mediated osteolysis | Quercetin (2 or 5 mg/kg/day)—14 days | BV/TV: ↑; total porosity: ↓; erosion area: ↓; osteoclast number: ↓ | [46] |
Female Sprague–Dawley rats | Bone defect (diameter: 4 mm) | Quercetin/silk fibroin/hydroxyapatite scaffold with bone-marrow-derived MSCs (implant)—6 weeks | BMD: ↑; BV: ↑; BV/TV: ↑; BS: ↑; Tb.N: ↑; Tb.Th: ↑; bone matrix: ↑; new collagenous tissue: ↑; tissue ingrowth: ↑ | [47] |
Female Sprague–Dawley rats | Calvarial bone defect (size: 5 × 4 mm) | Quercetin/duck’s foot collagen/hydroxyapatite sponge (25 μM)—8 weeks | BMD: ↑; BV: ↑; new bone formation: ↑ | [48] |
New Zealand rabbits | Parietal bone defect (size: 5 × 10 mm) | Quercetin solution mixed with collagen matrix—14 days | New bone formation: ↑ | [49,50] |
Female New Zealand white rabbits | Bone defect | Quercitrin nanocoated implant surface | CTSK: ↓; H+ ATPase: ↓; MMP-9: ↓; osteoprotegerin: ↔; RANKL: ↓; IL-10: ↔; TNF-α: ↔; ALP: ↔; LDH: ↔ | [51] |
Senescence-accelerated OXYS rats | - | Dihydroquercetin (5.06 mg/kg/day) + glucosamine alendronate (1.26 mg/kg/day)—2 months | BMD (total, lumbar and humerus): ↑; Fmax femur: ↑; femoral strength: ↑; CTX-1: ↓ | [52] |
Female rabbits | - | Quercetin (10 or 100 μg/kg, 3 times/week, i.m.)—90 days | Cr.Th: ↑ | [53] |
Type of Cell | Intervention | Research Findings | References |
---|---|---|---|
Rat bone-marrow-derived MSCs | Quercetin (0.1, 1 or 10 μmol/L) | Cell differentiation: ↑, ALP: ↑, COL1: ↑, osteocalcin: ↑, Cbfα1: ↑, TGF-β1: ↑, BMP-2: ↑, p-ERK1/2: ↑, p-p38: ↑, p-JNK: ↑ | [62] |
Rat bone-marrow-derived MSCs | Quercetin (1–10 μM) | Cell proliferation: ↑, ALP: ↑, calcium: ↑, Runx-2: ↑, COL1: ↑, BSP: ↑, osteopontin: ↑, osteocalcin: ↑, BMP-2: ↑, VEGF: ↑, ANG-1: ↑, p-ERK: ↑, p-p38: ↑, p-JNK: ↔ | [63] |
Rat bone-marrow-derived MSCs | Quercetin (1 μM) | ALP: ↑, Runx-2: ↑, COL1: ↑, BSP: ↑, osteopontin: ↑, osteocalcin: ↑, BMP-2: ↑, osteoprotegerin: ↑, RANKL: ↓, VEGF: ↑, ANG-1: ↑, TGF-β: ↑, bFGF: ↑, p-ERK: ↑, p-p38: ↑, p-JNK: ↔, p-Akt: ↑ | [34] |
Mouse bone-marrow-derived MSCs | Quercetin (0.1–5 μM) | Cell proliferation: ↑, ALP: ↑, mineralised nodules: ↑, Runx-2: ↑, osterix: ↑, osteopontin: ↑, BMP-2: ↑, Smad1: ↑, p-Smad1: ↑, Smad4: ↑, oestrogen receptor signalling: ↑ | [64] |
Mouse bone-marrow-derived MSCs | Quercetin (25–50 μM) | Cell proliferation: ↑, ALP: ↑, mineralisation: ↑, osteopontin: ↑, Runx-2: ↑, osteocalcin: ↑, osterix: ↑, osteoprotegerin: ↑ | [65] |
Mouse adipose stem cells | Quercetin (10–100 μM) | Osterix: ↑, Runx-2: ↑, COL1: ↑, BMP-2: ↑, osteopontin: ↑, osteocalcin: ↑ | [66] |
Human adipose-tissue-derived stromal cells | Quercetin (5 μM) | Osteogenic differentiation: ↑, ALP: ↑, Runx-2: ↑, BMP-2: ↑, osteopontin: ↑, p-ERK: ↑ | [67] |
Murine osteoblastic MC3T3-E1 cells | Quercetin (10–200 μM) | Cell proliferation: ↑ | [68] |
Calcium-deficient hydroxyapatite with quercetin | Osteoblast number: ↑, ALP: ↑, Runx-2: ↑, COL1: ↑, BSP: ↑, osteocalcin: ↑, calcium mineralisation: ↑ | ||
Murine osteoblastic MC3T3-E1 cells | Quercetin (10 μM) | ALP: ↑ | [50] |
Human osteoblast-like MG-63 cells | Quercetin (1–50 μM) | ALP: ↑, p-ERK: ↑; oestrogen receptor signalling: ↑ | [69] |
Rat osteoblast-like ROS 17/2.8 cells | Quercetin (5 μM) | BSP: ↑, Cbfα1/Runx-2: ↑ | [70] |
Quercetin 3-glucuronide (5 μM) | |||
Rat femoral-diaphyseal and -metaphyseal tissues | Quercetin (1 or 10 μM) | Calcium content: ↑ | [71] |
Osteoblasts derived from rat calvaria and bone marrow | Quercetin (10 μM) | BMP-2: ↑, COL1: ↑ | [33] |
Quercetin C-glucoside (10 or 100 mM) | ALP: ↑, mineralisation: ↑, Runx-2: ↑, BMP-2: ↑, osteocalcin: ↑, COL1: ↑ | ||
Stem-cell spheroids cultured in osteogenic medium | Quercetin (1 μg/mL) | ALP: ↑, Runx-2: ↑ | [72] |
Microspheres loaded with quercetin (1 μg/mL) | ALP: ↑, COL1: ↑, Runx-2: ↑ | ||
Human osteoblast-like MG-63 cells | Ethanolic fraction of Cissus quadrangularis enriched with rutin (65.36 ± 0.75 mg/g) and quercetin (1.06 ± 0.12 mg/g) | ALP: ↑, osteoprotegerin: ↑, RANKL: ↓, RANKL/osteoprotegerin ratio: ↓ | [73] |
Rat bone-marrow-derived MSCs treated with TNF-α | Quercetin (1 μM) | Cell viability: ↑, calcium nodule formation: ↑, Runx-2: ↑, osterix: ↑, pNF-κB: ↓, β-catenin: ↑ | [29] |
Murine osteoblastic MC3T3-E1 cells treated with TNF-α | Quercetin (10 μM) | Mineralisation: ↑, NF-κB: ↓, BMP-2- and TGF-β-induced SMAD activation: ↔ | [74] |
Murine osteoblastic MC3T3-E1 cells treated with LPS | Quercetin (10, 25 or 50 μM) | Mineralisation: ↑, ALP: ↑, osterix: ↑, Runx-2: ↑, osteocalcin: ↑, apoptotic cells: ↓, Bcl-2: ↑, Bcl-XL: ↑, caspase-3: ↓, Bax: ↓, cytochrome c: ↓, Wnt3: ↑, β-catenin: ↑, p-GSK3β: ↓, p-ERK1/2: ↑, p-p38: ↓ | [75] |
Murine osteoblastic MC3T3-E1 cells treated with LPS | Quercetin (5–10 μM) | ALP: ↑, osterix: ↑, Runx-2: ↑, COL1: ↑, osteocalcin: ↑, BSP: ↑, p-ERK1/2: ↑, p-JNK: ↓ | [76] |
Murine osteoblastic MC3T3-E1 cells treated with H2O2 or menadione | Quercetin (1–10 μM) | Cell viability: ↑ | [77] |
Primary human osteoblasts exposed to cigarette-smoke medium | Quercetin (25, 50 or 100 μM) | Cell viability: ↑, ROS: ↓, HO-1: ↑, SOD: ↑, p-Nrf2: ↑, p-ERK1/2: ↑ | [78] |
Osteoblasts isolated from fetal rat calvaria | Quercetin aglycone (20 μM) | CAT: ↑, GCLC: ↑, HO-1: ↑, Prdx5: ↑, Nrf2: ↔, p-ERK1/2: ↓, pNF-κB: ↓ | [79] |
Osteoblasts isolated from fetal rat calvaria treated with H2O2 | Quercetin aglycone (20 μM) | Mineralised nodules: ↑, Runx-2: ↑, ALP: ↑, BSP: ↑, osteocalcin: ↑, GCLC: ↓, HO-1: ↓ | [80] |
Human osteoblast-like SaOS-2 cells | Quercetin 3-β-D-glucoside (0.1 or 0.3 μM) + polyphosphate (3–100 μM) | Runx-2: ↑, ATF6: ↑, Ets1: ↑ | [81] |
Murine osteoblastic MC3T3-E1 cells treated with H2O2 | Quercitrin (1 μg/mL) | Cell growth: ↑, collagen: ↑, ALP: ↑, mineralisation: ↑, RANKL: ↓, MDA: ↓, protein carbonyl: ↓, nitrotyrosine: ↓ | [82] |
Murine osteoblastic MC3T3-E1 cells | Quercitrin (200 or 500 μM) | BSP: ↑, osteocalcin: ↑, osteoprotegerin: ↔, RANKL: ↓ | [83] |
Bone-marrow-derived MSCs | Quercetin/silk fibroin/hydroxyapatite scaffold | Cell growth and proliferation: ↑, ALP: ↑, COL1: ↑, osteocalcin: ↑, Runx-2: ↑ | [47] |
Bone-marrow-derived MSCs | Quercetin/duck’s foot collagen/hydroxyapatite sponge (25 μM) | Cell proliferation: ↑, ALP: ↑, COL1: ↑, osteocalcin: ↑, Runx-2: ↑ | [48] |
Co-culture model containing human osteoblast-like MG63 cells and osteoclast precursors 2T-110 treated with H2O2 | Quercetin-loaded hydroxyapatite | Cell viability of osteoblast: ↑, osteocalcin: ↑, Runx-2: ↑, LDH: ↓, TNF-α: ↓, ROS: ↓, cell viability of osteoclast: ↓, caspase 3: ↑ | [84] |
Triculture model containing human osteoblast-like MG63 cells, osteoclast precursors 2T-110 and HUVECs | Quercetin-loaded hydroxyapatite | Cell proliferation of osteoblast: ↑, ALP: ↑, COL1: ↑, osteocalcin: ↑, osteonectin: ↑, cell proliferation of osteoclast: ↓, osteoprotegerin: ↑, RANKL: ↓, osteoprotegerin/RANKL ratio: ↑, CTSK: ↓, TGF-β1: ↓, IL-6: ↓ | [85] |
Murine osteoblastic MC3T3-E1 cells | Quercetin vanadyl (IV) complexes | ALP: ↑, COL1: ↑, p-ERK: ↑ | [86] |
Human osteoblast-like MG-63 cells | Quercetin–copper (II) complexes (20–60 μM) | ALP: ↑, mineralised matrix: ↑, calcium deposition: ↑, Runx-2: ↑, COL1: ↑, pre-mir-15b: ↑, blood vessel size, length and junctions: ↑ | [87] |
MSCs | ADM-GO-PEG/quercetin (10 μM) scaffold | Cell proliferation: ↑, lipoprotein lipase: ↑, peroxisome proliferator-activated receptor-γ: ↑, ALP: ↑, Runx-2: ↑ | [88] |
Bone-marrow-derived MSCs | Quercitrin-nanocoated titanium surfaces | Cell viability: ↑, cell adhesion: ↑, calcium content: ↑, mineralisation: ↑ | [89] |
Murine osteoblastic MC3T3-E1 cells treated with TNF-α | Quercetin (1–10 μM) | Cell viability: ↓, cytotoxicity: ↑, apoptosis: ↑, Fas activation: ↑, PARP cleavage: ↑, Bcl-2: ↓, cytochrome c: ↓, degradation of procaspase-8: ↑, caspase-8: ↑, caspase-3: ↑, AP-1 activity: ↑, p-JNK: ↑ | [90,91] |
Rat calvarial osteoblast-like cells | Quercetin (0.1–10 μM) | Cell proliferation: ↓, ALP: ↓, osteocalcin: ↓, deposition of calcium: ↓, mineralised nodules: ↓, | [92] |
MSCs induced to differentiate into osteoblasts | Quercetin (10 μM) | Cell proliferation: ↓, ALP: ↓, mineralisation: ↓, COL1: ↓, osteocalcin: ↓ | [93] |
RAW264.7 cells treated with M-CSF and RANKL | Quercetin (6.3 or 25 μmol/L) | Area of osteoclast: ↓, TRAP-positive cells: ↓, bone resorption area: ↓, F-actin ring area and number: ↓, c-Fos: ↓, NFATc1: ↓, MMP-9: ↓, CTSK: ↓, IL-1β: ↓, TNF-α: ↓, IL-6: ↓, IL-10: ↑, Arg-1: ↑, iNOS: ↓ | [46] |
RAW264.7 cells treated with RANKL | Quercetin (10 μM) | TRAP-positive multinucleated cells: ↓, c-Fos: ↓, RANK: ↓, CalcR: ↓ | [94] |
RAW264.7 cells treated with M-CSF and RANKL | Quercetin (2–5 μM) | Osteoclast formation: ↓, pit formation: ↓, disruption of actin ring: ↑, TRAP activity: ↓ | [95] |
RAW264.7 cells treated with RANKL | Quercetin (0.1–25 μM) | Osteoclast number: ↓, NF-κB: ↓ | [74] |
RAW264.7 cells treated with RANKL | Quercetin (40–160 μmol/L) | Osteoclast number: ↓, cell apoptosis: ↓, PERK: ↓, IRE1: ↓, GRP78: ↓, CHOP: ↓, caspase-12: ↓, caspase-3: ↓, Bcl-2: ↑, TNF-α: ↓, IL-1β: ↓, IL-6: ↓, TRAP: ↓, RANK: ↓ | [45] |
RAW264.7 cells treated with RANKL | Quercetin (1–10 μM) | TRAP-positive multinucleated cells: ↓, CalcR: ↓, CTSK: ↓, MMP-9: ↓, NFATc1: ↓ | [31] |
Quercetin-3-O-β-D-glucuronide (1–10 μM) | TRAP-positive multinucleated cells: ↓ | ||
RAW264.7 cells treated with RANKL | Quercetin (10–200 μM) | Cell proliferation: ↓, osteoclast number: ↓ | [68] |
Calcium-deficient hydroxyapatite with quercetin | Cell proliferation: ↓, osteoclast number: ↓, TRAP activity: ↓ | ||
RAW264.7 cells treated with RANKL | Quercetin (1–10 μM) | TRAP-positive multinucleated cells: ↓, TRAP: ↓, NF-κB activation: ↓, AP-1 activation: ↓ | [96] |
Human PBMCs treated with M-CSF and RANKL | Osteoclast number: ↓, resorbed area: ↓, hydroxylysylpyridinoline: ↓ | ||
Bone-marrow macrophages treated with M-CSF and RANKL | Quercetin (10 or 20 μM) | TRAP-positive multinucleated cells: ↓, RANK: ↓, c-Fos: ↓ | [32] |
Quercetin-6-C-β-d-glucopyranoside (1 or 100 nM) | TRAP-positive multinucleated cells: ↓, RANK: ↓, c-Fos: ↓ | ||
Highly purified rabbit osteoclasts | Quercetin (50 μM) | Resorption pit area: ↓, hydroxylysylpyridinoline: ↓, apoptotic osteoclast: ↑, ROS: ↓ | [97] |
RAW264.7 cells treated with LPS | Quercetin (15, 25 or 50 μM) | Osteoclast number: ↓, TRAP: ↓, MMP-9: ↓, CTSK: ↓, RANK: ↓, COX-2: ↓, TRAF6: ↓, p38 MAPK: ↑, p-JNK: ↑, number of apoptotic cells: ↑, Bax: ↑, Bcl-2: ↓, number of pits: ↓ | [98] |
Mouse bone-marrow cells treated with PTH | Quercetin (0.01–1 μM) | Osteoclast number: ↓ | [71] |
RAW264.7 cells treated with LPS | Quercetin (0.03–3 μg/mL) | NO: ↓, ROS: ↓, TNF-α: ↓, IL-1β: ↓, IL-6: ↓ | [99] |
Quercitrin (0.045–4.5 (0.03–3 μg/mL) | |||
RAW264.7 cells treated with RANKL | Quercitrin (200 or 500 μM) | TRAP-positive multinucleated cells: ↓, resorption pit: ↓, TRAP: ↓, CTSK: ↓, alpha v intergrin: ↑, MMP-9: ↓, H+ ATPase: ↓, Dc-Stamp: ↓ | [83] |
RAW264.7 cells treated with RANKL | Quercitrin-nanocoated implant surface | TRAP: ↓, CalcR: ↓, CTSK: ↓, H+ ATPase: ↓, MMP-9: ↓ | [51] |
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Wong, S.K.; Chin, K.-Y.; Ima-Nirwana, S. Quercetin as an Agent for Protecting the Bone: A Review of the Current Evidence. Int. J. Mol. Sci. 2020, 21, 6448. https://doi.org/10.3390/ijms21176448
Wong SK, Chin K-Y, Ima-Nirwana S. Quercetin as an Agent for Protecting the Bone: A Review of the Current Evidence. International Journal of Molecular Sciences. 2020; 21(17):6448. https://doi.org/10.3390/ijms21176448
Chicago/Turabian StyleWong, Sok Kuan, Kok-Yong Chin, and Soelaiman Ima-Nirwana. 2020. "Quercetin as an Agent for Protecting the Bone: A Review of the Current Evidence" International Journal of Molecular Sciences 21, no. 17: 6448. https://doi.org/10.3390/ijms21176448