Alteration of Bone Status with Ascorbic Acid Deficiency in ODS (Osteogenic Disorder Shionogi) Rats

Togari, Akifumi; Arai, M.; Nakagawa, Shigeki; Banno, Akira; Aoki, Mikako; Matsumoto, Shosei

doi:10.1254/jjp.68.255

Cited by 27 publications

(19 citation statements)

References 15 publications

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“…ODS rats can not biosynthesize AsA due to their hereditary lack of L-gulonolactone oxidase (Mizushima et al, 1984), and they show remarkably reduced plasma AsA levels when fed an AsAdeficient diet (Miyajima et al, 1995;Togari et al, 1995). Rats of the experimental group were fed an AsA-deficient diet (F-2; Funabashi Farms, Chiba, Japan), with free access to water without AsA, for up to 4 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…Scorbutic guinea pig results in low levels of bone formation in leg bones and collagen synthesis in articular cartilage (Kipp et al, 1996), and leads to decreased expression of mRNAs for osteocalcin, alkaline phosphatase, and type I collagen, and to increased osteopontin expression in calvarial bone (Mahmoodian et al, 1996). Scorbutic rats are characterized by low body weight, small craniofacial size, and low concentrations of plasma alkaline phosphatase (Tsunenari et al, 1991;Miyajima et al, 1995;Togari et al, 1995). The leg bones and the tail vertebra show thin cortical bone and decreased volume of trabeculae accompanied by morphological alterations in epiphyseal cartilage (Tsunenari et al, 1991;Togari et al, 1995;Ellender and Gazelakis, 1996).…”

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confidence: 99%

“…Scorbutic rats are characterized by low body weight, small craniofacial size, and low concentrations of plasma alkaline phosphatase (Tsunenari et al, 1991;Miyajima et al, 1995;Togari et al, 1995). The leg bones and the tail vertebra show thin cortical bone and decreased volume of trabeculae accompanied by morphological alterations in epiphyseal cartilage (Tsunenari et al, 1991;Togari et al, 1995;Ellender and Gazelakis, 1996).…”

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confidence: 99%

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Morphological influence of ascorbic acid deficiency on endochondral ossification in osteogenic disorder Shionogi rat

Sakamoto

Takano

2002

Anat. Rec.

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The influences of chronic deficiency of L-ascorbic acid (AsA) on the differentiation of osteo-chondrogenic cells and the process of endochondral ossification were examined in the mandibular condyle and the tibial epiphysis and metaphysis by using Osteogenic Disorder Shionogi (ODS) rats that bear an inborn deficiency of L-gulonolactone oxidase. Weanling male rats were kept on an AsA-free diet for up to 4 weeks, until the symptoms of scurvy became evident. The tibiae and condylar processes of scorbutic rats displayed undersized and distorted profiles with thin cortical and scanty cancellous bones. In these scorbutic bones, the osteoblasts showed characteristic expanded round profiles of rough endoplasmic reticulum, and lay on the bone surface where the osteoid layer was missing. Trabeculae formation was deadlocked, although calcification of the cartilage matrix proceeded in both types of bone. Scorbutic condylar cartilage showed severe disorganization of cell zones, such as unusual thickening of the calcification zone, whereas the tibial cartilage showed no particular alterations (except for a moderately decreased population of chondrocytes). In condylar cartilage, hypertrophic chondrocytes were encased in a thickened calcification zone, and groups of nonhypertrophic chondrocytes occasionally formed cell nests surrounded by a metachromatic matrix in the hypertrophic cell zone. These results indicate that during endochondral ossification, chronic AsA deficiency depresses osteoblast function and disturbs the differentiation pathway of chondrocytes. The influence of scurvy on mandibular condyle cartilage is different from that on articular and epiphyseal cartilage of the tibia, suggesting that AsA plays different roles in endochondral ossification in the mandibular condyle and long bones. Anat Rec 268: 93-104, 2002.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Morphological influence of ascorbic acid deficiency on endochondral ossification in osteogenic disorder Shionogi rat

Sakamoto

Takano

2002

Anat. Rec.

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“…Inhibition of collagen synthesis by growing cells in the absence of ascorbic acid (AA) or through the use of specific inhibitors totally blocks osteoblast differentiation (1)(2)(3)(4)(5)(6). In vivo, both bone formation and osteoblast differentiation, as assessed by expression of osteocalcin (OCN) and alkaline phosphatase mRNAs, are also severely reduced in vitamin C-deficient animals (7,8). Thus, the ECM is an important, but poorly understood regulator of the osteoblast differentiation pathway.…”

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confidence: 99%

Role of the α2-Integrin in Osteoblast-specific Gene Expression and Activation of the Osf2 Transcription Factor

Xiao

Wang

Benson

et al. 1998

Journal of Biological Chemistry

343

292

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Extracellular matrix molecules such as type I collagen are required for the adhesion, migration, proliferation, and differentiation of a number of cell types including osteoblasts. Matrix components often affect cell function by interacting with members of the integrin family of cell surface receptors. Previous work showed that collagen matrix synthesis, induced by addition of ascorbic acid to cells, precedes and is essential for the expression of osteoblast markers and induction of the osteocalcin promoter in murine MC3T3-E1 cells. This later response requires OSE2, the promoter element recognized by Osf2 (also called Cbfa1/AML3/PEBP2␣A), a recently identified osteoblast-specific transcription factor. Osteoblasts express several integrins including ␣2␤1 which is a major receptor for type I collagen. This paper examines the role of the ␣ 2 -integrin subunit in osteocalcin promoter activation and osteoblast differentiation. Disruption of ␣ 2 -integrin-ECM interactions with a blocking antibody or DGEA peptide containing the cell-binding domain of type I collagen blocked activation of the mouse osteocalcin gene 2 promoter by ascorbic acid as well as induction of endogenous osteocalcin mRNA and mineralization. Furthermore, anti-␣ 2 -integrin blocking antibody or peptide reduced ascorbic aciddependent binding of Osf2 to OSE2 without affecting levels of transcription factor mRNA. Time course studies revealed that ascorbic acid-dependent binding of Osf2 to OSE2 preceded increases in osteocalcin and bone sialoprotein expression and this increase in Osf2 binding was not accompanied by comparable changes in levels of transcription factor mRNA or protein. Taken together, these studies demonstrate that an ␣ 2 -integrincollagen interaction is required for activation of Osf2 and induction of osteoblast-specific gene expression. Furthermore, matrix signals may regulate Osf2 through a post-translational pathway or via an accessory factor.As a cell primarily devoted to matrix production, the osteoblast must have the ability to monitor the composition of the extracellular matrix (ECM) 1 it is secreting as well as adapt matrix composition to the changing mechanical needs of bone. Consistent with the concept that there is a dialogue between the osteoblast and its ECM, osteoblast precursors must secrete a collagenous matrix before they will differentiate. Inhibition of collagen synthesis by growing cells in the absence of ascorbic acid (AA) or through the use of specific inhibitors totally blocks osteoblast differentiation (1-6). In vivo, both bone formation and osteoblast differentiation, as assessed by expression of osteocalcin (OCN) and alkaline phosphatase mRNAs, are also severely reduced in vitamin C-deficient animals (7, 8). Thus, the ECM is an important, but poorly understood regulator of the osteoblast differentiation pathway.Integrins are the principle mediators of the molecular dialogue between a cell and its ECM environment (for reviews, see Refs 9 and 10). These transmembrane receptors convey information from the ECM to ...

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“…Unlike humans, wild-type rats can synthesize ascorbic acid; osteogenic disorder shionogi (ODS) rats, however, carry a hereditary defect in ascorbic acid synthesis caused by the absence of l-gulonolactone oxidase, which catalyzes the conversion of l-gulono-lactone into ascorbic acid (18,19). ODS rats, when fed with an ascorbic acidfree diet, show low body weight, small craniofacial size, low concentrations of plasma alkaline phosphatase (ALPase) and defective bone formation (23,35,30,36). Accordingly, the hydroxyproline level in collagen synthesis (20) was also decreased (18).…”

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confidence: 99%

Morphological assessment of bone mineralization in tibial metaphyses of ascorbic acid-deficient ODS rats

Hasegawa

Hara

et al. 2011

Biomed. Res.

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Osteogenic disorder shionogi (ODS) rats carry a hereditary defect in ascorbic acid synthesis, mimicking human scurvy when fed with an ascorbic acid-deficient (aa-def) diet. As aa-def ODS rats were shown to feature disordered bone formation, we have examined the bone mineralization in this rat model. A fibrous tissue layer surrounding the trabeculae of tibial metaphyses was found in aa-def ODS rats, and this layer showed intense alkaline phosphatase activity and proliferating cell nuclear antigen-immunopositivity. Many osteoblasts detached from the bone surfaces and were characterized by round-shaped rough endoplasmic reticulum (rER), suggesting accumulation of malformed collagen inside the rER. Accordingly, fine, fragile fibrillar collagenous structures without evident striation were found in aa-def bones, which may result from misassembling of the triple helices of collagenous α-chains. Despite a marked reduction in bone formation, ascorbic acid deprivation seemed to have no effect on mineralization: while reduced in number, normal matrix vesicles and mineralized nodules could be seen in aa-def bones. Fine needle-like mineral crystals extended from these mineralized nodules, and were apparently bound to collagenous fibrillar structures. In summary, collagen mineralization seems unaffected by ascorbic acid deficiency in spite of the fine, fragile collagenous fibrils identified in the bones of our animal model. Ascorbic acid, i.e., vitamin C, is essential for the hydroxylation of proline and lysine in the α-chains that occurs in the rough endoplasmic reticulum (rER) during the process of collagen synthesis. Shortage of ascorbic acid may disrupt the process of crosslinking through which collagenous α-chains are bundled so as to form the stable helical structure known as superhelix (9, 28). Unlike humans, wild-type rats can synthesize ascorbic acid; osteogenic disorder shionogi (ODS) rats, however, carry a hereditary defect in ascorbic acid synthesis caused by the absence of l-gulonolactone oxidase, which catalyzes the conversion of l-gulono-lactone into ascorbic acid (18,19). ODS rats, when fed with an ascorbic acidfree diet, show low body weight, small craniofacial size, low concentrations of plasma alkaline phosphatase (ALPase) and defective bone formation (23,35,30,36). Accordingly, the hydroxyproline level in collagen synthesis (20) was also decreased (18). Since type I collagen accounts for approximately 90% of the organic fraction of bone (15), the deficiency of ascorbic acid in ODS rats results in reduced bone formation accompanied by deleterious effects in bone mechanical properties (14,30,36).

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Alteration of Bone Status with Ascorbic Acid Deficiency in ODS (Osteogenic Disorder Shionogi) Rats

Cited by 27 publications

References 15 publications

Morphological influence of ascorbic acid deficiency on endochondral ossification in osteogenic disorder Shionogi rat

Morphological influence of ascorbic acid deficiency on endochondral ossification in osteogenic disorder Shionogi rat

Role of the α2-Integrin in Osteoblast-specific Gene Expression and Activation of the Osf2 Transcription Factor

Morphological assessment of bone mineralization in tibial metaphyses of ascorbic acid-deficient ODS rats

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