The Dual Role of Oat Bran Water Extract in Bone Homeostasis Through the Regulation of Osteoclastogenesis and Osteoblast Differentiation

The number of patients with bone metabolic disorders including osteoporosis is increasing worldwide. These disorders often facilitate bone fractures, which seriously impact the patient’s quality of life and could lead to further health complications. Bone homeostasis is tightly regulated to balance bone resorption and formation. However, many anti-osteoporotic agents are broadly categorized as either bone forming or anti-resorptive, and their therapeutic use is often limited due to unwanted side effects. Therefore, safe and effective therapeutic agents are needed for osteoporosis. This study aims to clarify the bone protecting effects of oat bran water extract (OBWE) and its mode of action. OBWE inhibited RANKL (receptor activator of nuclear factor-κB ligand)-induced osteoclast differentiation by blocking c-Fos/NFATc1 through the alteration of I-κB. Furthermore, we found that OBWE enhanced BMP-2-stimulated osteoblast differentiation by the induction of Runx2 via Smad signaling molecules. In addition, the anti-osteoporotic activity of OBWE was also evaluated using an in vivo model. OBWE significantly restored ovariectomy-induced bone loss. These in vitro and in vivo results showed that OBWE has the potential to prevent and treat bone metabolic disorders including osteoporosis.

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The Dual Role of Oat Bran Water Extract in Bone Homeostasis Through the Regulation of Osteoclastogenesis and Osteoblast Differentiation

10.20944/preprints201811.0363.v1 ◽

2018 ◽

Author(s):

Shin-Hye Kim ◽

Kwang-Jin Kim ◽

Hyeon Jung Kang ◽

Young-Jin Son ◽

Sik-Won Choi ◽

...

Keyword(s):

Osteoblast Differentiation ◽

Metabolic Disorders ◽

Bone Fractures ◽

Osteoclast Differentiation ◽

Water Extract ◽

In Vivo Model ◽

Bone Homeostasis ◽

Number Of Patients ◽

Oat Bran

The number of patients with bone metabolic disorders including osteoporosis is increasing worldwide. These disorders often facilitate bone fractures, which seriously impact the patient’s quality of life and could lead to further health complications. Bone homeostasis is tightly regulated to balance bone resorption and formation. However, many anti-osteoporotic agents are broadly categorized as either bone forming or anti-resorptive, and their therapeutic use is often limited due to unwanted side effects. Therefore, safe and effective therapeutic agents are needed for osteoporosis. This study aims to clarify the bone protecting effects of oat bran water extract (OBWE) and its mode of action. OBWE inhibited RANKL-induced osteoclast differentiation by blocking c-Fos/NFATc1 through the alteration of I-κB. Furthermore, we found that OBWE enhanced BMP-2-stimulated osteoblast differentiation by the induction of Runx2 via Smad signaling molecules. In addition, the anti-osteoporotic activity of OBWE was also evaluated using an in vivo model. OBWE significantly restored ovariectomy-induced bone loss. These in vitro and in vivo results showed that OBWE has the potential to combat bone metabolic disorders including osteoporosis

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Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival

The Journal of Cell Biology ◽

10.1083/jcb.201204067 ◽

2012 ◽

Vol 199 (7) ◽

pp. 1145-1158 ◽

Cited By ~ 42

Author(s):

Hyung Joon Kim ◽

Vikram Prasad ◽

Seok-Won Hyung ◽

Zang Hee Lee ◽

Sang-Won Lee ◽

...

Keyword(s):

Plasma Membrane ◽

Bone Mass ◽

Osteoclast Differentiation ◽

Premenopausal Women ◽

Fine Tuning ◽

Bone Homeostasis ◽

Regulatory Loop ◽

And Function

The precise regulation of Ca2+ dynamics is crucial for proper differentiation and function of osteoclasts. Here we show the involvement of plasma membrane Ca2+ ATPase (PMCA) isoforms 1 and 4 in osteoclastogenesis. In immature/undifferentiated cells, PMCAs inhibited receptor activator of NF-κB ligand–induced Ca2+ oscillations and osteoclast differentiation in vitro. Interestingly, nuclear factor of activated T cell c1 (NFATc1) directly stimulated PMCA transcription, whereas the PMCA-mediated Ca2+ efflux prevented NFATc1 activation, forming a negative regulatory loop. PMCA4 also had an anti-osteoclastogenic effect by reducing NO, which facilitates preosteoclast fusion. In addition to their role in immature cells, increased expression of PMCAs in mature osteoclasts prevented osteoclast apoptosis both in vitro and in vivo. Mice heterozygous for PMCA1 or null for PMCA4 showed an osteopenic phenotype with more osteoclasts on bone surface. Furthermore, PMCA4 expression levels correlated with peak bone mass in premenopausal women. Thus, our results suggest that PMCAs play important roles for the regulation of bone homeostasis in both mice and humans by modulating Ca2+ signaling in osteoclasts.

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PIP5k1β controls bone homeostasis through modulating both osteoclast and osteoblast differentiation

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjz028 ◽

2019 ◽

Vol 12 (1) ◽

pp. 55-70 ◽

Cited By ~ 3

Author(s):

Xiaoying Zhao ◽

Penglei Cui ◽

Guoli Hu ◽

Chuandong Wang ◽

Lei Jiang ◽

...

Keyword(s):

Osteoblast Differentiation ◽

Nuclear Translocation ◽

Osteoclast Differentiation ◽

Bone Homeostasis ◽

Osteoporosis Prevention ◽

Cytoskeletal Organization ◽

Fos Expression ◽

And Migration ◽

And Function ◽

Proliferation And Migration

Abstract PIP5k1β is crucial to the generation of phosphotidylinosotol (4, 5)P2. PIP5k1β participates in numerous cellular activities, such as B cell and platelet activation, cell phagocytosis and endocytosis, cell apoptosis, and cytoskeletal organization. In the present work, we aimed to examine the function of PIP5k1β in osteoclastogenesis and osteogenesis to provide promising strategies for osteoporosis prevention and treatment. We discovered that PIP5k1β deletion in mice resulted in obvious bone loss and that PIP5k1β was highly expressed during both osteoclast and osteoblast differentiation. Deletion of the gene was found to enhance the proliferation and migration of bone marrow-derived macrophage-like cells to promote osteoclast differentiation. PIP5k1β−/− osteoclasts exhibited normal cytoskeleton architecture but stronger resorption activity. PIP5k1β deficiency also promoted activation of mitogen-activated kinase and Akt signaling, enhanced TRAF6 and c-Fos expression, facilitated the expression and nuclear translocation of NFATC1, and upregulated Grb2 expression, thereby accelerating osteoclast differentiation and function. Finally, PIP5k1β enhanced osteoblast differentiation by upregulating master gene expression through triggering smad1/5/8 signaling. Therefore, PIP5k1β modulates bone homeostasis and remodeling.

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Anti-Müllerian Hormone Negatively Regulates Osteoclast Differentiation by Suppressing the Receptor Activator of Nuclear Factor-κB Ligand Pathway

Journal of Bone Metabolism ◽

10.11005/jbm.2021.28.3.223 ◽

2021 ◽

Vol 28 (3) ◽

pp. 223-230

Author(s):

Jung Ha Kim ◽

Yong Ryoul Yang ◽

Ki-Sun Kwon ◽

Nacksung Kim

Keyword(s):

Osteoblast Differentiation ◽

Bone Cells ◽

Osteoclast Differentiation ◽

Nuclear Factor Κb ◽

Bone Morphogenetic Protein 2 ◽

Tartrate Resistant Acid Phosphatase ◽

Nuclear Factor ◽

Bone Homeostasis ◽

Alizarin Red ◽

Receptor Activator

Background: Multiple members of the transforming growth factor-β (TGF-β) superfamily have well-established roles in bone homeostasis. Anti-Müllerian hormone (AMH) is a member of TGF-β superfamily of glycoproteins that is responsible for the regression of fetal Müllerian ducts and the transcription inhibition of gonadal steroidogenic enzymes. However, the involvement of AMH in bone remodeling is unknown. Therefore, we investigated whether AMH has an effect on bone cells as other TGF-β superfamily members do.Methods: To identify the roles of AMH in bone cells, we administered AMH during osteoblast and osteoclast differentiation, cultured the cells, and then stained the cultured cells with Alizarin red and tartrate-resistant acid phosphatase, respectively. We analyzed the expression of osteoblast- or osteoclast-related genes using real-time polymerase chain reaction and western blot.Results: AMH does not affect bone morphogenetic protein 2-mediated osteoblast differentiation but inhibits receptor activator of nuclear factor-κB (NF-κB) ligand-induced osteoclast differentiation. The inhibitory effect of AMH on osteoclast differentiation is mediated by IκB-NF-κB signaling.Conclusions: AMH negatively regulates osteoclast differentiation without affecting osteoblast differentiation.

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Knockdown of SERPINB2 enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the Wnt/β-catenin signalling pathway

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02581-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kai Hang ◽

Li Ying ◽

Jinwu Bai ◽

Yibo Wang ◽

Zhihui Kuang ◽

...

Keyword(s):

Fracture Healing ◽

Osteogenic Differentiation ◽

Bone Fracture ◽

Osteoblast Differentiation ◽

Tibial Fracture ◽

Bone Fractures ◽

Bone Fracture Healing ◽

Non Union

Abstract Background Globally, bone fractures are the most common musculoskeletal trauma, and approximately 8–10% of cases that fall into the categories of delayed or non-union healing. To date, there are no efficient pharmacological agents to accelerate the healing of bone fractures. Thus, it is necessary to find new strategies that accelerate bone healing and reduce the incidence of non-union or delayed fracture healing. Previous studies have revealed that the plasminogen activation system has been demonstrated to play an important role in bone metabolism. However, the function of SERPINB2 in the osteogenesis of hBMSCs remains unclear. Therefore, in this study, we investigated the effects and mechanism of SERPINB2 on osteogenic differentiation. Methods We investigated the osteogenesis effects of hBMSCs by both exogenous SerpinB2 protein and SERPINB2 gene silencing in vitro. Cell proliferation assay was used to assess the effect of exogenous SerpinB2 or SERPINB2 silencing on proliferation of hBMSCs. qPCR and Western blotting analysis detected the expression of target genes and proteins respectively. ALP staining was used to evaluated ALP activity and Alizarin Red staining (ARS) was used to evaluate mineral deposition. In vivo, a murie tibial fracture model was established, histological evaluation and radiographic analysis was used to confirm the therapeutic effects of SERPINB2 silencing in fracture healing. Statistical significance between two groups was determined by Student’s t test, one-way ANOVA or Bonferroni’s post-hoc test according to the distribution of the tested population. Results The addition of exogenous SerpinB2 protein inhibted osteoblast differentiation of hBMSCs in vitro, while SERPINB2 gene silencing significant promote osteoblast differentiation of hBMSCs in vitro. And silenced SERPINB2 gene also increased mineral deposits. Moreover, β-catenin levels were up-regulated by SERPINB2 gene depletion. And the enhancement of osteogenic differentiation induced by SERPINB2 silencing was almost inhibited by specific Wnt/β-catenin signaling pathway inhibitor. In a murine tibial fracture model, local injection of SERPINB2 siRNA improved bone fracture healing. Conclusions Taken together, these findings indicate that SERPINB2 silencing promoted osteogenic differentiation of BMSCs via the Wnt/β-catenin signaling pathway, and silenced SERPINB2 in vivo effectively promotes fracture healing, suggesting that SERPINB2 may be a novel target for bone fracture healing.

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PIP5k1 β controls bone homeostasis through modulating both osteoclast and osteoblast differentiation

10.1101/288910 ◽

2018 ◽

Author(s):

Xiaoying Zhao ◽

Guoli Hu ◽

Chuandong Wang ◽

Lei Jiang ◽

Jingyu Zhao ◽

...

Keyword(s):

Osteoblast Differentiation ◽

Nuclear Translocation ◽

Osteoclast Differentiation ◽

Bone Homeostasis ◽

Osteoporosis Prevention ◽

Genes Expression ◽

And Migration ◽

And Function ◽

Insight Into ◽

Proliferation And Migration

AbstractPIP5K1β is crucial to generation of phosphotidylinosotol (4, 5) P2. PIP5K1β participates in numerous cellular activities, such as B cell and platelet activation, cell phagocytosis and endocytosis, cell apoptosis, and cytoskeletal organization. In the present work, we aimed to make insight into the function of PIP5K1β in osteoclastogenesis and osteogenesis to provide promising strategies for osteoporosis prevention and treatment. We discovered that PIP5k1β deletion in mice resulted in obvious bone loss and PIP5K1β was highly expressed both during osteoclast and osteoblast differentiation, besides, PIP5K1β deletion enhanced the proliferation and migration of BMMs to promote osteoclast differentiation. PIP5k1β−/− osteoclast exhibited normal cytoskeleton architecture but stronger resorption activity. PIP5k1β deficiency also promoted activation of MAPK and Akt signaling, enhanced TRAF6 and c-Fos expression, facilitated the expression and nuclear translocation of NFATC1 and upregulated Grb2 expression, thereby accelerating osteoclast differentiation and function. Finally, PIP5K1β enhanced osteoblast differentiation by upregulating master genes expression through triggering smad1/5/8 signaling. Thereby, PIP5K1β modulate bone homeostasis and remodeling.

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The Inhibitory Effect of Alisol A 24-Acetate fromAlisma canaliculatumon Osteoclastogenesis

International Journal of Endocrinology ◽

10.1155/2015/132436 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Kwang-Jin Kim ◽

Alain Simplice Leutou ◽

Jeong-Tae Yeon ◽

Sik-Won Choi ◽

Seong Hwan Kim ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Essential Role ◽

Bone Fractures ◽

Osteoclast Differentiation ◽

Cathepsin K ◽

Osteoporosis Treatment ◽

Inhibitory Effect ◽

New Drugs ◽

Multinucleated Cells ◽

Number Of Patients

Osteoporosis is a disease that decreases bone mass. The number of patients with osteoporosis has been increasing, including an increase in patients with bone fractures, which lead to higher medical costs. Osteoporosis treatment is all-important in preventing bone loss. One strategy for osteoporosis treatment is to inhibit osteoclastogenesis. Osteoclasts are bone-resorbing multinucleated cells, and overactive osteoclasts and/or their increased number are observed in bone disorders including osteoporosis and rheumatoid arthritis. Bioactivity-guided fractionations led to the isolation of alisol A 24-acetate from the dried tuber ofAlisma canaliculatum. Alisol A 24-acetate inhibited RANKL-mediated osteoclast differentiation by downregulating NFATc1, which plays an essential role in osteoclast differentiation. Furthermore, it inhibited the expression of DC-STAMP and cathepsin K, which are related to cell-cell fusion of osteoclasts and bone resorption, respectively. Therefore, alisol A 24-acetate could be developed as a new structural scaffold for inhibitors of osteoclast differentiation in order to develop new drugs against osteoporosis.

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Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

Molecular and Cellular Biology ◽

10.1128/mcb.01075-15 ◽

2016 ◽

Vol 36 (19) ◽

pp. 2451-2463 ◽

Cited By ~ 13

Author(s):

Takashi Iezaki ◽

Kazuya Fukasawa ◽

Gyujin Park ◽

Tetsuhiro Horie ◽

Takashi Kanayama ◽

...

Keyword(s):

Bone Loss ◽

Osteoclast Differentiation ◽

Nuclear Factor Κb ◽

Bone Diseases ◽

Nuclear Factor ◽

Activator Protein 1 ◽

Bone Homeostasis ◽

Activated T Cells

Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we show that the transcriptional coactivator/repressor interferon-related developmental regulator 1 (Ifrd1) is expressed in osteoclast lineages and represents a component of the machinery that regulates bone homeostasis. Ifrd1 expression was transcriptionally regulated in preosteoclasts by receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) through activator protein 1. Global deletion of murineIfrd1increased bone formation and decreased bone resorption, leading to a higher bone mass. Deletion ofIfrd1in osteoclast precursors prevented RANKL-induced bone loss, although no bone loss was observed under normal physiological conditions. RANKL-dependent osteoclastogenesis was impairedin vitroinIfrd1-deleted bone marrow macrophages (BMMs).Ifrd1deficiency increased the acetylation of p65 at residues K122 and K123 via the inhibition of histone deacetylase-dependent deacetylation in BMMs. This repressed the NF-κB-dependent transcription of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), an essential regulator of osteoclastogenesis. These findings suggest that an Ifrd1/NF-κB/NFATc1 axis plays a pivotal role in bone remodelingin vivoand represents a therapeutic target for bone diseases.

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NLRP12 provides a critical checkpoint for osteoclast differentiation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1500196112 ◽

2015 ◽

Vol 112 (33) ◽

pp. 10455-10460 ◽

Cited By ~ 14

Author(s):

Jennifer L. Krauss ◽

Rong Zeng ◽

Cynthia L. Hickman-Brecks ◽

Justin E. Wilson ◽

Jenny P.-Y. Ting ◽

...

Keyword(s):

Nuclear Factor Kappa B ◽

Nuclear Translocation ◽

Osteoclast Differentiation ◽

Disease Model ◽

Nuclear Factor ◽

Bone Homeostasis ◽

Genetic Ablation ◽

Nuclear Factor Kappa

The alternative or noncanonical nuclear factor kappa B (NF-κB) pathway regulates the osteoclast (OC) response to receptor activator of nuclear factor kappa B ligand (RANKL) and thus bone metabolism. Although several lines of evidence support the emerging concept that nucleotide-binding leucine-rich repeat and pyrin domain-containing receptor 12 (NLRP12) impedes alternative NF-κB activation in innate immune cells, a functional role for NLRP12 outside an inflammatory disease model has yet to be reported. Our study demonstrates that NLRP12 has a protective role in bone via suppression of alternative NF-κB–induced osteoclastogenesis and is down-modulated in response to osteoclastogenic stimuli. Here, we show that retroviral overexpression of NLRP12 suppressed RelB nuclear translocation and OC formation. Conversely, genetic ablation of NLRP12 promoted NIK stabilization, RelB nuclear translocation, and increased osteoclastogenesis in vitro. Using radiation chimeras, we demonstrated these in vitro observations dovetail with our in vivo findings that NLRP12 deficiency leads to enhanced OC numbers accompanied by a significant decline in bone mass under physiological conditions. Consistent with the basal bone phenotype, we also observed an enhanced osteolytic response following RANKL injection over the calvaria of NLRP12-deficient chimeric mice compared with wild-type control mice. Thus, modulation of NLRP12 levels controls alternative NF-κB signaling in OC precursors, altering bone homeostasis and osteolytic responses.

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