Selection of malonate‐resistant stromal cell‐derived osteoprogenitor cells in vitro

Klein, Benjamin Y.; Gal, I.; Segal, David

doi:10.1002/jcb.240510211

Cited by 21 publications

(10 citation statements)

References 14 publications

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“…The effect of DF 1222 on mineralization is similar to that of malonate, which is structurally related to tartronates (tartronic acid is hydroxymalonic acid), as recently reported by Klein et al (29) These authors demonstrated that malonate is able to stimulate mineralization in rat marrow stromal cells. The mechanism that is the basis of this effect should be the inhibition of succinate dehydrogenase (SDH, complex II) 30 in agreement with the hypothesis that cells destined to mineralize rely less on respiration. (31) However, the inhibition of Krebs enzymes in actively resorbing osteoclast could reduce their activity, as indirectly indicated by the stimulatory or inhibitory effects on osteoblastic SDH exerted by PTH (32) or calcitonin, (33) respectively.…”

Section: Discussionsupporting

confidence: 82%

Tartronates: A New Generation of Drugs Affecting Bone Metabolism

Caselli

Mantovanini

Gandolfi

et al. 1997

Journal of Bone and Mineral Research

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In the search for a new class of bone-sparing agents for treating osteopenic disorders, we hypothesized that tartronic acid derivatives, sharing the chemical characteristics both of bisphosphonates and of Gla residues contained in matrix proteins such as osteocalcin, could positively affect bone metabolism. A series of tartronates was therefore tested for their ability to affect bone metabolism. In vitro resorption tests were performed examining pit formation by freshly isolated rat and rabbit osteoclasts plated onto bone slices and exposed to the drugs for 48 h. Tartronates bearing a linear side-chain (DF 1222 and DF 1363A) were the most effective in inhibiting pit excavation in the pM-nM range. Tartronates did not affect osteoclast viability, number, adhesion, or tartrate resistant acid phosphatase activity. Transient cell retraction was observed in osteoclasts plated onto glass and exposed to DF 1222. The maximal effect was seen in cells treated for 4 h at a concentration of 1 pM. DF 1222 accelerated mineralization in cultures of periosteal cells without affecting other osteoblast-like functions. This product was therefore tested in vivo in ovariectomized mice. Bone mass in femur was evaluated, by ash gravimetry, 21 days after ovariectomy. Unfortunately, DF 1222, the most active of tartronates in vitro, was inactive in this test because of its high hydrophilicity and the subsequent too short residence time. On the contrary, its tetrahydropyranyl ether derivative, DF 1363A, endowed with a significantly higher lipophilicity, showed a dose-dependent bone-sparing effect when administered subcutaneously at 10, 30, and 100 mg/kg/die, thus confirming the activity seen in in vitro tests. Because of their feasible parallel effect on both bone resorption and formation, tartronate derivatives may be tested to candidate this class of products for clinical studies. (J Bone Miner Res 1997;12:972-981)

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Section: Discussionsupporting

confidence: 82%

Tartronates: A New Generation of Drugs Affecting Bone Metabolism

Caselli

Mantovanini

Gandolfi

et al. 1997

Journal of Bone and Mineral Research

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“…Changes in intracellular distribution of ceramide may shorten Bcl-2 halflife via dephosphorylation by PP2 at the mitochondria level [Ruvolo et al, 1999] and thereby tilt the Bax/Bcl-2 ratio in favor of apoptosis. As yet an unsorted issue is on one hand the involvement of Bax and Bcl-2 in the mitochondrial participation in apoptosis and on the other hand the involvement of the mitochondria in the initiation of bone matrix mineralization [Klein et al, 1993b]. It has been suggested that the cellmediated mineralization is associated with uncoupling that enables thermogenesis [Klein et al, 1996a].…”

Section: Discussionmentioning

confidence: 99%

Cell death in cultured human Saos2 osteoblasts exposed to low‐density lipoprotein

Klein

Rojansky

Ben‐Yehuda

et al. 2003

J of Cellular Biochemistry

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Osteoporosis (OP) and atherosclerotic-cardiovascular diseases (and possibly dementia) constitute emerging age-related co-morbidity states that might share risk factors. Blood-born lipids, like LDL involved in atherosclerosis and apolipoprotein-E4 (ApoE4) involved in dementia, may also be implicated in development of OP. We examined osteoblast cell lines as a culture model for OP by exposure to lipoproteins. ApoE expression in Saos2 and U2OS osteoblasts was confirmed by PCR. ApoE4 did decrease cell counts relatively to ApoE3, especially in Saos2 cells in which it was less selective for cells with higher alkaline phosphatase (ALP, an osteoblast marker) activity than ApoE3. This associates with ApoE4, being a risk factor for both dementia and OP. Saos2, but not U2OS, showed a decrease in cell counts after 48 h exposure to native LDL (NLDL). Both cell lines had decreased cell counts already after 24 h when exposed to oxidized-LDL (OxLDL) for which Saos2 also showed a higher sensitivity than U2OS. Exposure of Saos2 to both, OxLDL at low concentration (5 microg/ml) and NLDL revealed a shrunken size cell fraction of 17-23% on the fluorescence-activated cell sorter (FACS) analysis. Such shrunken cell fraction was not seen when Saos2 cells were exposed to 50 microg/ml of OxLDL or to OxLDL combined with 10 nM dexamethasone (DEX, a stimulator of osteoprogenitor differentiation). DEX treatment has lysed the cells earlier than 24 h post exposure and has selected more resistant cells that did not show apoptotic shrinkage in the FACS analysis done after 24 h. We interpret this as a failure to detect the apoptotic cell fraction due to their lysis prior to the FACS analysis. Western blots performed at different time points (10 min, 30 min, 4 h, 24 h, and 48 h) under OxLDL + DEX revealed a fall in the positive regulator of pp60Src-kinase phosphotyrosine (pY)418 relative to the DEX controls during the first 4 h. This is consistent with DEX osteogenic induction, known to be negatively regulated by c-Src, although the pY418/pY529 ratios (negative/positive kinase regulation) fell only at the 10 min time point. Contrarily the pY418/pY529 ratio increased, relative to untreated controls, under 5 microg/ml and 50 microg/ml of NLDL at the 4 h time point and under 50 microg/ml NLDL only at the 10 min time point, being consistent with the ability of a higher dose of LDL to antagonize osteoblast differentiation. This could be even more acceptable if the NLDL would have become minimally oxidized during its long purification procedure. Under NLDL, the Bcl-2/Bax ratio was pro-apoptotic at 10 min, 30 min, and 4 h only under 50 microg/ml, whereas under OxLDL + DEX it was pro-apoptotic only after 4 h suggesting that additional pathways contribute to cell death. These results indicate that lipid effects on human osteoblast lines in culture may be used as a model to identify molecular targets shared between OP and atherosclerosis for intervention in this co-morbidity.

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“…A previous study reported enhanced lipogenesis was found in IUGR piglets (He et al., ). Malonate, as a competitive inhibitor, acts against succinate dehydrogenase in the respiratory electron transport chain within the TCA cycle (Klein, Gal, & Segal, ). A lower level of malonate was observed in the Arg group than in the CG group, resulting in a pronounced metabolism disturbance of the TCA cycle in the foetus.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic profiling in umbilical venous plasma reveals effects of dietary rumen‐protected arginine or N‐carbamylglutamate supplementation in nutrient‐restricted Hu sheep during pregnancy

Sun

Zhang

Fan

et al. 2017

Reprod Domestic Animals

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Maternal nutrient restriction during pregnancy is a major problem worldwide for human and animal production. Arginine (Arg) is critical to health, growth and reproduction. N-carbamylglutamate (NCG), a key enzyme in arginine synthesis, is not extensively degraded in rumen. The aim of this study was to investigate ameliorating effects of rumen-protected arginine (RP-Arg) and NCG supplementation on dietary in undernourished Hu sheep during gestation. From day 35 to 110 of gestation, 32 Hu ewes carrying twin foetuses were randomly divided into four groups: a control (CG) group (n = 8; fed 100% National Research Council (NRC) requirements for pregnant sheep), a nutrient-restricted (RG) group (n = 8; fed 50% NRC requirements, which included 50% mineral-vitamin mixture) and two treatment (Arg and NCG) groups (n = 8; fed 50% NRC requirements supplemented with 20 g/day RP-Arg or 5 g/day NCG, which included 50% mineral-vitamin mixture). The umbilical venous plasma samples of foetus were tested by H-nuclear magnetic resonance. Thirty-two differential metabolites were identified, indicating altered metabolic pathways of amino acid, carbohydrate and energy, lipids and oxidative stress metabolism among the four groups. Our results demonstrate that the beneficial effect of dietary RP-Arg and NCG supplementation on mammalian reproduction is associated with complex metabolic networks.

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Selection of malonate‐resistant stromal cell‐derived osteoprogenitor cells in vitro

Cited by 21 publications

References 14 publications

Tartronates: A New Generation of Drugs Affecting Bone Metabolism

Tartronates: A New Generation of Drugs Affecting Bone Metabolism

Cell death in cultured human Saos2 osteoblasts exposed to low‐density lipoprotein

Metabolomic profiling in umbilical venous plasma reveals effects of dietary rumen‐protected arginine or N‐carbamylglutamate supplementation in nutrient‐restricted Hu sheep during pregnancy

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