Luteolin attenuates glucocorticoid‐induced osteoporosis by regulating ERK/Lrp‐5/GSK‐3β signaling pathway in vivo and in vitro

Abstract

Glucocorticoid-induced osteoporosis (GIO) is a secondary osteoporosis with extensive use of glucocorticoids (GCs). GCs can increase bone fragility and fracture via inhibiting osteoblastic proliferation and differentiation. Luteolin (LUT), a kind of plant flavonoid, has been reported to exhibit the antioxidant activity, but the effects of LUT on GIO still remain unclear. This study aimed to investigate the effects of LUT on GIO both in vivo and in vitro and elaborate the potential molecular mechanisms. LUT increased the superoxide dismutase activity, glutathione level and decreased reactive oxygen species (ROS) level and lactate dehydrogenase release in GIO. Meanwhile, LUT decreased caspase-3, caspase-9, and Bax protein expressions and increased Bcl-2 protein expression in GIO. LUT increased the ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor-κB Ligand (RANKL) messenger RNA (mRNA) expression and mRNA expression levels of osteogenic markers, including runt-related transcription factor 2, osterix, collagen type I, and osteocalcin. LUT also enhanced the extracellular signal-regulated kinases (ERK) phosphorylation, glycogen synthase kinase 3β (GSK-3β) phosphorylation, mRNA expression levels of lipoprotein-receptor-related protein 5 (Lrp-5) and β-catenin. Further study revealed that Lrp-5 small interfering RNA (siRNA )and ERK-siRNA reduced the effects of LUT on GSK-3β phosphorylation, alkaline phosphatase (ALP) activity and the ratio of OPG/RANKL mRNA expression. Moreover, ERK-siRNA decreased Lrp-5 mRNA expression in vitro. These results indicated that LUT promoted proliferation by attenuating oxidative stress and promoted osteoblastic differentiation by regulating the ERK/Lrp-5/GSK-3β pathway in GIO. This study may bring to light the possible mechanisms involved in the action of LUT in GIO treatment, and benefit for further research on GIO.

The effect of luteolin in prevention of periodontal disease in Wistar rats

“…In addition, Jing et al. demonstrated decreased apoptosis and increased osteoblast differentiation via ERK/Lrp‐5/GSK‐3β pathway and elevated osteogenic markers, runt related x‐2, ALP, and osteoprotegerin/RANKL ratio after administration of 25, 50, and 100 mg/kg luteolin in rats with osteoporosis . Reduced MMP‐9 and MMP‐13 levels which indicate decreased collagen degradation, were also found in osteoblast cells subjected to luteolin .…”

“…Luteolin is a plant‐derived compound with a proven anti‐osteoclastic and anti‐inflammatory activity . ‒ Therefore, based on the evidence present in the literature, ‒ present study hypothesized that “Luteolin, would prevent periodontal disease by decreasing inflammation and bone loss and increasing osteoblastic activity.” Therefore, present study aimed to evaluate possible effects of two different doses of luteolin on experimentally induced periodontitis model in rats. To achieve this purpose, morphometrical evaluation of mandibles, inflammatory cell counts, osteoblast and TRAP‐positive osteoclast cell counts, and immunohistochemical determination of inducible nitric oxide synthase (iNOS), bone morphogenetic protein (BMP)‐2, MMP‐8, tissue inhibitor of MMP (TIMP)‐1, RANKL, and osteoprotegerin (OPG) levels were performed.…”

Emerging Natural-Product-Based Treatments for the Management of Osteoarthritis

“…In vitro studies have demonstrated that luteolin upregulates the expression of osteoblastic differentiation markers, including TGF-β1, BMP7, Runx-2, ALP, Osc, Osx, and collagen type I [34,88,89]. It also has anti-oxidative and anti-apoptotic effects on osteoblasts, in part via the regulation of the ERK/Lrp-5/GSK-3β signaling pathway [90][91][92]. Furthermore, luteolin diminishes osteoclastic differentiation and function in vitro and in vivo, increasing the bone mineral density and content of trabecular and cortical bones in ovariectomized rats [93,94].…”

Influence of olive oil and its components on mesenchymal stem cell biology

“…Yet, other authors using the same cellular type but much lower concentrations of this flavonoid have found that it prevented the osteoblastogenesis inhibition induced by glucocorticoids. Indeed, they showed that luteolin prevented bone mass loss, by downregulating apoptotic genes, increasing OPG / RANKL gene expression ratio, and activating the beta-catenin pathway in an animal model of osteoporosis induced by glucocorticoids[115]. Therefore, these results suggest that this compound has an osteoprotective role in bone marrow.…”