Hypergravity Stimulates Osteoblast Phenotype Expression: A Therapeutic Hint for Disuse Bone Atrophy

Morita, Sadao; Nakamura, Hiroshi; Kumei, Yasuhiro; Shimokawa, Hitoyata; Ohya, Keiichi; Shinomiya, Kenichi

doi:10.1196/annals.1329.020

Cited by 16 publications

(14 citation statements)

References 5 publications

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“…The finding that the OSVDR antiresorptive phenotype was not evident on endocortical or periosteal surfaces is consistent with effects of the transgene to locally reduce the bone proresorptive response to a systemic rise in active hormonal vitamin D levels. Mechanical load–responsive alterations in VDR expression have been reported, with microgravity suppressing (22) and hypergravity stimulating VDR activity (23) . These recent reports are consistent with our earlier observation of increased periosteal bone formation and enhanced mid‐diaphyseal diameter and strength in OSVDR long bones, which suggested enhanced load responsiveness in OSVDR cortical bone (13) .…”

Section: Discussionsupporting

confidence: 89%

Vitamin D Action and Regulation of Bone Remodeling: Suppression of Osteoclastogenesis by the Mature Osteoblast

Baldock

Thomas

Hodge

et al. 2006

Journal of Bone and Mineral Research

155

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Vitamin D acts through the immature osteoblast to stimulate osteoclastogenesis. Transgenic elevation of VDR in mature osteoblasts was found to inhibit osteoclastogenesis associated with an altered OPG response. This inhibition was confined to cancellous bone. This study indicates that vitamin D-mediated osteoclastogenesis is regulated locally by OPG production in the mature osteoblast.Introduction: Vitamin D stimulates osteoclastogenesis acting through its nuclear receptor (VDR) in immature osteoblast/stromal cells. This mobilization of calcium stores does not occur in a random manner, with bone preferentially removed from cancellous bone. The process whereby the systemic, humoral regulator is targeted to a particular region of the skeleton is unclear. Materials and Methods: Bone resorption was assessed in mice with vitamin D receptor transgenically elevated in mature osteoblasts (OSVDR). Vitamin D-mediated osteoclastogenesis was examined in vitro using OSVDR osteoblasts and osteoblastic RANKL: osteoprotegerin (OPG) examined in vivo and in vitro after vitamin D treatment. Results: Vitamin D-mediated osteoclastogenesis was reduced in OSVDR mice on chow and calciumrestricted diets, with effects confined to cancellous bone. OSVDR osteoblasts had a reduced capacity to support osteoclastogenesis in culture. The vitamin D-mediated reduction in OPG expression was reduced in OSVDR osteoblasts in vivo and in vitro, resulting in a reduced RANKL/OPG ratio in OSVDR compared with wildtype, after exposure to vitamin D. Conclusions: Mature osteoblasts play an inhibitory role in bone resorption, with active vitamin D metabolites acting through the VDR to increase OPG. This inhibition is less active in cancellous bone, effectively targeting this region for resorption after the systemic release of activated vitamin D metabolites.

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Section: Discussionsupporting

confidence: 89%

Vitamin D Action and Regulation of Bone Remodeling: Suppression of Osteoclastogenesis by the Mature Osteoblast

Baldock

Thomas

Hodge

et al. 2006

Journal of Bone and Mineral Research

155

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“…Fitzgerald obtained the same results after centrifugation (maximum of 3 g) for 3 h (Hughes-Fulford 2003). These results indicated that a small magnitude mechanical stimulation can alter mRNA levels in osteoblastic cells; however, these results were in sharp contrast with the results obtained from longer and higher level of hypergravity (Morita et al 2004). Furutsu et al (2000) found bidirectional effects of hypergravity on the growth and differentiated functions exist in ROS17/2.8 cells according to the magnitude of the hypergravity.…”

Section: Discussioncontrasting

confidence: 83%

Altered Actin Dynamics and Functions of Osteoblast-Like Cells in Parabolic Flight may Involve ERK1/2

Dai

Tan

Yang

et al. 2010

Microgravity Sci. Technol.

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Osteoblasts are sensitive to mechanical stressors such as gravity and alter their cytoskeletons and functions to adapt; however, the contribution of gravity to this phenomenon is not well understood. In this study, we investigated the effects of acute gravitational changes on the structure and function of osteoblast ROS17/2.8 as generated by parabolic flight. The changes in microfilament cytoskeleton was observed by immunofluorescence stain of Texas red conjugated Phalloidin and Alexa Fluor 488 conjugated DNase I for F-actin and G-actin, respectively. To examine osteoblast function, ALP (alkaline phosphatase) activity, osteocalcin secretions and the expression of ALP, COL1A1 (collagen type I alpha 1 chain) and osteocalcin were detected by modified Gomori methods, radioimmunity and RT-PCR, respectively. Double fluorescence staining of phosphorylated p44/42 and F-actin were performed to observe their colocalization relationship. The established semi-quantitative analysis method of fluorescence intensity of EGFP was used to detect the activity changes of COL1A1 promoter in EGFP-ROS cells with MAPK inhibitor PD98059 or F-actin inhibitor cytochalasin B. Results indicate that the altered gravity induced the reorganization of microfilament cytoskeletons of osteoblasts. After 3 h parabolic flight, F-actin of osteoblast cytoskeleton became thicker and directivity, whereas G-actin shrunk and became more concentrated at the edge of nucleus. The excretion of osteocalcin, the activity of ALP and the expression of mRNA decreased. Colocalization analysis indicated that phosphorylated p44/42 MAPK was coupled with F-actin. Inhibitor PD98059 and cytochalasin B decreased the fluorescence intensity of EGFP-ROS cells. Above results suggest that short time gravity variations induce the adjustment of osteoblast structure and functional and ERK1/2 signaling maybe involve these responses. We believe that it is an adaptive method of the osteoblasts to gravity alteration that structure alteration inhibits the function performing.

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“…Osteoblastic MG-63 cells show a decreased response to 1,25(OH) 2 D 3 under microgravity (2,18,26). Exposure to 12G hypergravity increases the mRNA expression of VDR and its target gene, osteocalcin, in rat osteoblasts (23). Thus microgravity decreases and hypergravity increases expression of some VDR target genes.…”

Section: Discussionmentioning

confidence: 97%

Hypergravity modulates vitamin D receptor target gene mRNA expression in mice

Ishizawa

Iwasaki²,

Kato³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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The possibility of pathological calcium metabolism is a critical health concern introduced by long-term space travel. Because vitamin D plays an important role in calcium homeostasis, we evaluated the effects of hypergravity on the expression of genes involved in vitamin D and calcium metabolism in ICR mice. When exposed to 2G hypergravity for 2 days, the mRNA expression of renal 25-hydroxyvitamin D 24-hydroxylase (Cyp24a1) was increased and that of 25-hydroxyvitamin D 1␣-hydroxylase (Cyp27b1) was decreased. Although hypergravity decreased food intake and increased the expression of starvation-induced genes, the changes in Cyp24a1 and Cyp27b1 expression were not due to starvation, suggesting that hypergravity affects these genes directly. Hypergravity decreased plasma 1␣,25-dihydroxyvitamin D3 levels in ICR mice, suggesting a consequence of decreased Cyp27b1 and increased Cyp24a1 expression. Although 1␣-hydroxyvitamin D3 [1␣(OH)D3] treatment induced the expression of vitamin D receptor (VDR) target genes in the kidney of 2G-exposed ICR mice to similar levels as controls, 1␣(OH)D3 increased the intestinal expression of Cyp24a1 in ICR mice. Hypergravity-dependent changes of Cyp24a1 and Cyp27b1 expression were diminished in mice exposed to hypergravity for 14 days, which may represent an adaptation to hypergravity stress. Hypergravity exposure also increased Cyp24a1 expression in the kidney of C57BL/6J mice. We examined the effects of hypergravity on VDRnull mice and found that renal Cyp27b1 expression in VDR-null mice was decreased by hypergravity while renal Cyp24a1 expression was not detected in VDR-null mice. Thus hypergravity modifies the expression of genes involved in vitamin D metabolism. 12), and vitamin D 2 is less effective than vitamin D 3 in maintaining serum 25(OH)D levels (1). Vitamin D deficiency, mainly caused by inadequate sun exposure, results in rickets and osteomalacia, and is also associated with increased risk of cancer, autoimmune disease, infection, and cardiovascular disease (10). 1,25(OH) 2 D 3 exhibits physiological and pharmacological effects by binding to the vitamin D receptor (VDR; NR1I1), a transcription factor of the nuclear receptor superfamily, which is highly expressed in the target organs of calcium homeostasis, such as the intestine, bone, kidney, and parathyroid glands (6, 21). VDR regulates the expression of many target genes, including 25-hydroxyvitamin D 24-hydroxylase (CYP24A1), calbindin D9k, and transient receptor potential vanilloid type 6 (TRPV6).Bone mineral loss is one of the critical health concerns raised by the prospect of long-term space travel (19,29). Space flight induces uncoupled bone remodeling, including increased bone resorption and urinary calcium excretion and decreased calcium absorption. Vitamin D deficiency due to the absence of ultraviolet light and decreased dietary intake of vitamin D during space flight has been considered to be one reason for dysregulated bone and calcium metabolism (30). Supplemental vitamin D and calcium intake increase blood...

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Hypergravity Stimulates Osteoblast Phenotype Expression: A Therapeutic Hint for Disuse Bone Atrophy

Cited by 16 publications

References 5 publications

Vitamin D Action and Regulation of Bone Remodeling: Suppression of Osteoclastogenesis by the Mature Osteoblast

Vitamin D Action and Regulation of Bone Remodeling: Suppression of Osteoclastogenesis by the Mature Osteoblast

Altered Actin Dynamics and Functions of Osteoblast-Like Cells in Parabolic Flight may Involve ERK1/2

Hypergravity modulates vitamin D receptor target gene mRNA expression in mice

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