Deficiency of CIZ, a nucleocytoplasmic shuttling protein, prevents unloading-induced bone loss through the enhancement of osteoblastic bone formation in vivo

Bone ◽  
2007 ◽  
Vol 40 (4) ◽  
pp. 852-860 ◽  
Author(s):  
K. Hino ◽  
T. Nakamoto ◽  
A. Nifuji ◽  
M. Morinobu ◽  
H. Yamamoto ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Nucleocytoplasmic Shuttling ◽  
Osteoblastic Bone Formation

scholarly journals Enhancement of Osteoclastic Bone Resorption and Suppression of Osteoblastic Bone Formation in Response to Reduced Mechanical Stress Do Not Occur in the Absence of Osteopontin

2001 ◽  
Vol 193 (3) ◽  
pp. 399-404 ◽  
Author(s):  
Muneaki Ishijima ◽  
Susan R. Rittling ◽  
Teruhito Yamashita ◽  
Kunikazu Tsuji ◽  
Hisashi Kurosawa ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Mechanical Stress ◽  
Bone Matrix ◽  
Osteoclastic Bone Resorption ◽  
Tail Suspension ◽  
Wild Type ◽  
Osteoblastic Bone Formation

Reduced mechanical stress to bone in bedridden patients and astronauts leads to bone loss and increase in fracture risk which is one of the major medical and health issues in modern aging society and space medicine. However, no molecule involved in the mechanisms underlying this phenomenon has been identified to date. Osteopontin (OPN) is one of the major noncollagenous proteins in bone matrix, but its function in mediating physical-force effects on bone in vivo has not been known. To investigate the possible requirement for OPN in the transduction of mechanical signaling in bone metabolism in vivo, we examined the effect of unloading on the bones of OPN−/− mice using a tail suspension model. In contrast to the tail suspension–induced bone loss in wild-type mice, OPN−/− mice did not lose bone. Elevation of urinary deoxypyridinoline levels due to unloading was observed in wild-type but not in OPN−/− mice. Analysis of the mechanisms of OPN deficiency–dependent reduction in bone on the cellular basis resulted in two unexpected findings. First, osteoclasts, which were increased by unloading in wild-type mice, were not increased by tail suspension in OPN−/− mice. Second, measures of osteoblastic bone formation, which were decreased in wild-type mice by unloading, were not altered in OPN−/− mice. These observations indicate that the presence of OPN is a prerequisite for the activation of osteoclastic bone resorption and for the reduction in osteoblastic bone formation in unloaded mice. Thus, OPN is a molecule required for the bone loss induced by mechanical stress that regulates the functions of osteoblasts and osteoclasts.

scholarly journals Novel Osteogenic Factors derived from Functional Food: Role in Prevention of Osteoporosis

2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Masayoshi Yamaguchi
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Functional Food ◽  
Human Subjects ◽  
Osteoclastic Bone Resorption ◽  
Bone Homeostasis ◽  
Osteoblastic Bone Formation ◽  
Prevention Of Osteoporosis ◽  
Osteogenic Effect

<p>Bone homeostasis is maintained through a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Bone loss is caused by decreasing in osteoblastic bone formation and increase in osteoclastic bone resorption, thereby leading to osteoporosis. Functional food factors may play a role in<br />the prevention of osteoporosis. Functional food factors including genistein, menaquinone-7 (vitamin K2) and β-cryptoxanthine have been shown to possess a potential osteogenic effect. These factors have been shown to reveal stimulatory effects on osteoblastic bone formation and suppressive effects on osteoclastic<br />bone resorption. Dietary intake of these factors has been shown to reveal preventive effects on bone loss in animal models of osteoporosis and human subjects. This review will introduce our findings concerning roles of functional food factors in regulation of bone homeostasis and prevention of osteoporosis.</p>

scholarly journals 3579 The role of CypD/mPTP during osteogenic differentiation - a potential target to prevent bone loss

2019 ◽  
Vol 3 (s1) ◽  
pp. 24-24
Author(s):  
Rubens Sautchuk ◽  
Brianna H. Shares ◽  
Roman A. Eliseev
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Mitochondrial Function ◽  
Ectopic Bone Formation ◽  
Regulatory Mechanisms ◽  
Mrna Levels ◽  
Prevent Bone Loss ◽  
Ectopic Bone

OBJECTIVES/SPECIFIC AIMS: The study aims to further investigate how cyclophilin D (CypD), the key mPTP opening regulator, affects BMSCs fate and to determine potential regulatory mechanisms involved in CypD regulation during osteogenesis. METHODS/STUDY POPULATION: We evaluated CypD mRNA expression in mouse BMSCs and in osteogenic-like (OL) cells during the course of OB differentiation. CypD protein level was also probed. Moreover, BMSCs had their mPTP activity recorded during osteoinduction. We further analyzed the effect of CypD genetic deletion on osteogenesis in vitro and in vivo. For our in vivo model, we performed the ectopic bone formation assay to asses differences in ossicle formation when CypD KO BMSCs were transplanted compared to wild type littermate BMSCs. In our in vitro model, we transfected OL cells with either CypD gain of function or CypD loss of function vector and measured their osteogenic differentiation potential. Additionally, we treated BMSCs with CypD inhibitor and compare to non-treated BMSCs for mineralization level. To determine potential regulatory mechanisms involved in CypD regulation, we analyzed the CypD gene (Ppif) promoter for potential transcription factor (TF) binding sites and found multiple Smad-binding elements within this promoter. Smads (Smad1, 5, 8) are TFs downstream from Bone Morphogenic Protein (BMP) signaling pathway that transmit cell differentiation signaling, and exert either activating or inhibitory effects on a variety of genes. We also transfect OL cells with Smad1 vector and analyzed for CypD mRNA levels. RESULTS/ANTICIPATED RESULTS: - Our data showed that CypD mRNA levels decreased in both primary cells and OL cells at day 7 and day 14 in osteogenic media. - Osteogenic induction also decreased mPTP activity. - In vivo ectopic bone formation assay showed increased ossicle fo DISCUSSION/SIGNIFICANCE OF IMPACT: Our data suggest that downregulation of CypD increases OB differentiation due to improved OxPhos activity led by mPTP closure. Our results corroborate reports of CypD downregulation and mPTP closure during neuronal differentiation in developing rat brains as well as in cardiomyocyte differentiation in developing mouse hearts. Our studies also suggest a yet unknown mechanism linking differentiation signaling with mitochondrial function – BMP/Smad mediated downregulation of CypD transcription. As initially mentioned, in a previous study, our lab showed that CypD KO mice present higher mitochondrial function and osteogenicity in aged BMSCs and less osteoporosis burden. Taken together, these results suggest that CypD can be a potential target to prevent bone loss in aging.

scholarly journals Germinated soy germ with increased soyasaponin Ab improves BMP-2-induced bone formation and protects against in vivo bone loss in osteoporosis

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Chan-Woong Choi ◽  
Sik-Won Choi ◽  
Han-Jun Kim ◽  
Kwang-Sik Lee ◽  
Shin-Hye Kim ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation

scholarly journals The nucleocytoplasmic shuttling protein CIZ reduces adult bone mass by inhibiting bone morphogenetic protein–induced bone formation

2005 ◽  
Vol 201 (6) ◽  
pp. 961-970 ◽  
Author(s):  
Mikihiko Morinobu ◽  
Tetsuya Nakamoto ◽  
Kazunori Hino ◽  
Kunikazu Tsuji ◽  
Zhong-Jian Shen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Bone Mass ◽  
Mrna Expression ◽  
Bone Marrow Cells ◽  
Nucleocytoplasmic Shuttling ◽  
Morphogenetic Protein ◽  
Adult Bone ◽  
Deficient Mice

Osteoporosis is a major health problem; however, the mechanisms regulating adult bone mass are poorly understood. Cas-interacting zinc finger protein (CIZ) is a nucleocytoplasmic shuttling protein that localizes at cell adhesion plaques that form where osteoblasts attach to substrate. To investigate the potential role of CIZ in regulating adult bone mass, we examined the bones in CIZ-deficient mice. Bone volume was increased and the rates of bone formation were increased in CIZ-deficient mice, whereas bone resorption was not altered. CIZ deficiency enhanced the levels of mRNA expression of genes encoding proteins related to osteoblastic phenotypes, such as alkaline phosphatase (ALP) as well as osterix mRNA expression in whole long bones. Bone marrow cells obtained from the femora of CIZ-deficient mice revealed higher ALP activity in culture and formed more mineralized nodules than wild-type cells. CIZ deficiency enhanced bone morphogenetic protein (BMP)–induced osteoblastic differentiation in bone marrow cells in cultures, indicating that BMP is the target of CIZ action. CIZ deficiency increased newly formed bone mass after femoral bone marrow ablation in vivo. Finally, BMP-2–induced bone formation on adult mouse calvariae in vivo was enhanced by CIZ deficiency. These results establish that CIZ suppresses the levels of adult bone mass through inhibition of BMP-induced activation of osteoblasts.

scholarly journals Mechanical Loading Shows Anti-Myeloma Effects While Rescuing Bone Loss with Net Bone Formation in a Myeloma Bone Disease Murine Model

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3164-3164
Author(s):  
Fani Ziouti ◽  
Maximilian Rummler ◽  
Andreas Brandl ◽  
Andreas Beilhack ◽  
Maureen Lynch ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Remodeling ◽  
Mechanical Loading ◽  
Bone Disease ◽  
Whole Body ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mechanical Stimuli

Abstract Osteolytic bone disease (BD) is a hallmark of multiple myeloma (MM) with tumor cells in the bone marrow shifting the balance of the bone remodeling process towards massive bone resorption. As a result, patients develop devastating osteolytic lesions that lead to non-healing bone fractures and pain, affecting life quality and mortality rates. Bones have the capacity to adapt mass and structure to mechanical stimuli, as dramatically seen in young tennis athletes with muscle-bone asymmetries in the playing arm. We have previously shown that tibial mechanical loading rescued bone loss in our murine MOPC315.BM MM model with an advanced osteolytic phenotype. Here, we hypothesize that mechanical strain (1) modulates the bone microenvironment and (2) has antitumor activity in mice. (1) We determined bone formation and bone resorption parameters by time-lapsed microCT analysis to show how skeletal mechanical stimuli control MM bone disease (MMBD) progression over time. (2) To monitor tumor progression, we used non-invasive bioluminescence imaging (BLI) and enzyme-linked immunosorbent assay (ELISA) for detection of MOPC315.BM specific immunoglobulin A (IgA) levels. In our in vivo loading study, we injected MOPC315.BM cells intratibially (i.t.) in BALB/c mice to establish MMBD (n=17) and used PBS-injected (n=13) as well as noninjected mice (n=8) as controls. Eight (MM), seven (PBS) and 8 (noninjected) mice received compressive tibial loading for three weeks while nine (MM) and six (PBS) mice served as nonloaded controls. The bone remodeling response to mechanical loading was investigated by longitudinal in vivo microCT imaging performed every 5 days (at day 13, 18, 23, 28, and 33 after i.t. injection). MicroCT images from day 33 were geometrically registered onto images of day 13 and resampled into the same coordinate system using Amira and scripts written in Matlab for post-processing. Normalized newly mineralized and eroded bone volume (MV/BV, EV/BV), normalized formed and eroded bone surface area (MS/BS, ES/BS), mineralized thickness (MTh) and eroded depth (ED) were quantified. ANOVA was performed to examine the effect of loading and injection. Loading significantly increased the periosteal MV/BV, periosteal and endosteal MS/BS as well as decreased the periosteal EV/BV and periosteal and endocortical ES/BS. Endosteal MV/BV or EV/BV were not affected, which may be due to differences in the local strain environment at the two surfaces. In addition, mechanical stimuli did not influence ED, but led to diminished periosteal EV/BV and periosteal ES/BS suggesting fewer resorption sites in tibiae subjected to loading. Injection significantly affected periosteal and endosteal bone formation and resorption (Fig.1). Significant increases in cortical bone mass of loaded MM mice were accompanied by decreases in tumor load as evidenced by MOPC315.BM specific IgA levels (Fig. 2A). Interestingly, quantification of tibial and whole body bioluminescence signal intensities revealed controlled tumor growth in the loaded left tibia and a further delay of tumor cell dissemination throughout body of MM mice (Fig. 2B). Our data provide evidence that skeletal mechanical stimuli have anti-myeloma effects and rescue osteolytic bone loss in MMBD. The anabolic response to mechanical loads outweighs the anti-resorptive effect of MM cells, suggesting a combination of loading with bone resorption inhibitors in future therapeutic strategies. Disclosures No relevant conflicts of interest to declare.

scholarly journals HDAC6 inactivates Runx2 promoter to block osteogenesis of bone marrow stromal cells in age-related bone loss of mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chao Ma ◽  
Juan Gao ◽  
Jun Liang ◽  
Weixiang Dai ◽  
Zhenfei Wang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Differentiation Potential ◽  
Runx2 Expression ◽  
Aged Mice ◽  
Age Related ◽  
Old Mice

Abstract Background Senile osteoporosis can cause bone fragility and increased risk for fractures and has been one of the most prevalent and severe diseases affecting the elderly population worldwidely. The underlying mechanisms are currently intensive areas of investigation. In age-related bone loss, decreased bone formation overweighs increased bone resorption. The molecular mechanisms underlying defective bone formation in age-related bone loss are not completely understood. In particular, the specific role of histone acetylation in age-related bone loss has not been examined thoroughly. Methods We employed 6- and 18-month-old mice to investigate the mechanisms of defective bone formation in age-related bone loss. Bone marrow stromal cells (BMSCs) were induced to undergo in vitro osteogenic differentiation. Chromatin immunoprecipitation (ChIP) was used to investigate the binding of histone deacetylases (HDACs) on Runx2 promoter in BMSCs. Luciferase reporter and transient transfection assay were employed to study Runx2 gene expression modulation by HDAC and androgen receptor (AR). siRNA and HDAC6 inhibitor, Tubastatin A, were used to inhibit HDAC6 in vitro. And systemic administration of Tubastatin A was used to block HDAC6 in vivo. Results Age-related trabecular bone loss was observed in 18-month-old mice compared with 6-month-old mice. In vitro osteogenic differentiation potential of BMSCs from 18-month-old mice was weaker than 6-month-old mice, in which there was Runx2 expression inactivation in BMSCs of 18-month-old mice compared with 6-month-old mice, which was attributable to HDAC6-mediated histone hypoacetylation in Runx2 promoter. There was competitive binding of HDAC6 and AR on Runx2 promoter to modulate Runx2 expression in BMSCs. More importantly, through siRNA- or specific inhibitor-mediated HDAC6 inhibition, we could activate Runx2 expression, rescue in vitro osteogenesis potential of BMSCs, and alleviate in vivo age-related bone loss of mice. Conclusion HDAC6 accumulation and histone hypoacetylation on Runx2 promoter contributed to the attenuation of in vitro osteogenic differentiation potential of BMSCs from aged mice. Through HDAC6 inhibition, we could activate Runx2 expression and osteogenic differentiation potential of BMSCs from aged mice and alleviate the age-related bone loss of aged mice. Our study will benefit not only for understanding the age-related bone loss, but also for finding new therapies to treat senile osteoporosis.

scholarly journals Preventive Effects of Chrysanthemum coronarium L. Extract on Bone Metabolism In Vitro and In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
So Ah Kim ◽  
Ae Sin Lee ◽  
Haeng Jeon Hur ◽  
Sang Hee Lee ◽  
Mi Jeong Sung
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Cell Line ◽  
Bone Fractures ◽  
Transmembrane Protein ◽  
Osteoclast Differentiation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Chrysanthemum Coronarium

Osteoporosis is characterized by decreased bone mass and bone microarchitectural failure, leading to an enhanced risk of bone fractures. Chrysanthemum coronarium L. (CC) is a natural plant with powerful antioxidant activity. This study investigated the antiosteoporotic effects of CC extracts in in vitro cell cultures and in vivo bone loss animal models. CC stimulated osteoblast differentiation and mineralized bone formation by osteoblasts by increasing the expression of bone formation markers (alkaline phosphatase, osteoprotegerin, and osteoprotegerin/receptor activator nuclear factor-κB ligand ratio) in the murine preosteoblastic cell line MC3T3-E1. Additionally, CC was found to inhibit osteoclast differentiation by downregulating bone resorption markers (tartrate-resistant acid phosphatase, cathepsin K, dendritic cell-specific transmembrane protein, and calcitonin receptor) in the murine macrophage-like cell line RAW264.7. CC prevented ovariectomy-induced bone loss, preserved trabecular microarchitecture, and improved serum bone turnover markers in an osteoporotic mouse model. These findings suggest that CC extract may be considered as a natural therapeutic or preventive agent for osteoporotic bone loss.

scholarly journals Morroniside promotes the osteogenesis by activating PI3K/Akt/mTOR signaling

2021 ◽  
Vol 85 (2) ◽  
pp. 332-339
Author(s):  
Hui Liu ◽  
Xi Li ◽  
Jingui Lin ◽  
Miaokuo Lin
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Mtor Signaling ◽  
Detailed Mechanism ◽  
Pharmacological Inhibition ◽  
Prevent Bone Loss ◽  
In Vivo Assays ◽  
Ovariectomized Mice

ABSTRACT Morroniside exerts a proosteogenic effect, which can prevent bone loss. However, the detailed mechanism underlying Morroniside-regulated bone formation is unclear. Morroniside can maintain cell homeostasis by promoting PI3K/Akt/mTOR signaling. The purpose of this study is to explore the significance of PI3K/Akt/mTOR signaling in Morroniside-regulated osteogenesis. The results showed that Morroniside promoted the activities of PI3K, Akt, and mTOR in osteoblast precursor MC3T3-E1. The differentiation of MC3T3-E1 to mature osteoblasts promoted by Morroniside can be reversed by the pharmacological inhibition of PI3K or mTOR. Importantly, in the presence of Morroniside, the osteoblast differentiation suppressed by PI3K inhibitor was reversed by mTOR overexpression. In vivo assays showed that in bone tissue of ovariectomized mice, Morroniside-enhanced osteoblast formation was reversed by the pharmacological inhibition of PI3K or mTOR. In conclusion, Morroniside can promote the osteogenesis through PI3K/Akt/mTOR signaling, which provides a novel clue for the strategy of Morroniside in treating osteoporosis.

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