Protective effect of pentoxifylline on growth plate in neonatal rats following long-term phototherapy.
Phototherapy alters growth plate structure.
"Sixty weanling Sprague-Dawley rats were randomly separated into three equal groups. Group A, the control group, did not receive phototherapy and pentoxifylline. Groups B and C were exposed to phototherapy for 7 d. In addition to phototherapy, group C was also given pentoxifylline during the study period. Compared with zonal lengths on d 7 after initiation of phototherapy, group B had significantly lower values than group A for all zonal lengths. Zonal lengths of growth plate were increased significantly with pentoxifylline treatment in group C for 7 d compared with group B. After phototherapy, group B had significantly higher values than groups A and C for plasma malondialdehyde levels. The pentoxifylline was found here to have some potential to reduce the effects of phototherapy on growth plate in neonatal rats at a relatively low dose."
"No correlations were found between malondialdehyde levels and growth plate zonal lengths in group A."
"pentoxifylline reduces oxygen radical production and protects against tissue damage in vivo by the action of its metabolites"
Saturday, July 25, 2009
Metabolics of Chondrogenesis
Metabolomic Analysis of Differential Changes in Metabolites during ATP Oscillations in Chondrogenesis.
"Prechondrogenic condensation is a critical step for skeletal pattern formation. ATP oscillations play an essential role in prechondrogenic condensation{Maybe LSJL can mimic these ATP oscillations to induce prechondrogenic condensation}. 93 cationic and 109 anionic compounds derived from known metabolic pathways [are involved in chondrogenesis]. 15 cationic and 18 anionic compounds revealed significant change between peak and trough of ATP oscillations. Glycolysis, mitochondrial respiration and uronic acid pathway oscillate in phase with ATP oscillations, while PPRP and nucleotides synthesis pathways oscillate in antiphase with ATP oscillations. ATP-producing glycolysis and mitochondrial respiration oscillate in antiphase with the ATP-consuming PPRP/nucleotide synthesis pathway during chondrogenesis. "
"extracellular ATP and cAMP/PKA signaling mediate ATP oscillations during chondrogenesis"
"ATP oscillations were generated 2–4 d after chondrogenic induction"
"Besides ATP, 3 cationic compounds such as O-acetylcarnitine, phosphorylcholine, and tyramine and 11 anionic compounds such as fructose 1,6-bisphosphate, malate, fumaric acid, 2-oxoglutarate,cis-aconitic acid, 1,3-bisphosphoglycerate, 2-phosphoglycerate, 3-phosphoglycerate, NADH,UDP-glucuronic acid, and glucuronic acid were significantly increased at the peak of PACTIN-PxRe oscillations"<-These compounds likely oscillate along with ATP.
Carnitine related genes upregulated by LSJL:
Down:
Crat
Cpt1b
Choline genes Up:
Lrat
Chrna4
Chrna3
Down:
Cdc2l5
Pafah1b2
Gnb1
Chrna10
Aytl1
Malate genes Up:
Me3
NADH genes Down:
Ndufb8
"glycolysis and TCA cycle oscillate during ATP oscillations."
"glycolytic and mitochondrial oscillations are interdependent on each other."
"NADH oscillates in phase with ATP oscillations."
"oscillatory activity of carnitine O-acetyltransferase may mediate prechondrogenic condensation by modulating cellular proliferation."
"uridine diphosphate (UDP)-glucuronic acid and glucuronic acid were significantly increased in the peak of ATP oscillations. UDP-glucuronic acid is the active form of glucuronic acid for the incorporation of glucuronic acid into chondroitin sulphate. UDP-glucuronic acid is produced from glucose via uronic acid pathway: glucose 6-phosphate is isomerized to glucose 1-phosphate, which then reacts with uridine triphosphate (UTP) to form UDP glucose in a reaction catalyzed by UDP-glucose pyrophosphorylase, and subsequently UDP glucose is oxidized by NAD-dependent UDP-glucose dehydrogenase to yield UDP-glucuronic acid"
"ATP oscillations lead to prechondrogenic condensation by inducing oscillatory secretion of adhesion molecules and ECM involved in cell-cell adhesion"
"Ca2+ influx was shown to mediate ATP oscillations in chondrogenesis"
"12 cationic compounds such as diethanolamine, glycine, guanine, cyclohexylamine, glutamine, aspartic acid, 2-aminoisobutyric acid, methionine sulfoxide, proline, threonine, asparagine, and hydroxyproline and 6 anionic compounds such as phosphoribosylpyrophosphate (PPRP), ADP, dCTP, UDP, GMP, and cGMP were significantly increased in the trough of PACTIN-PxRe oscillations"
Genes in LSJL involved in Glycolysis according to Gene Ontology:
The chemical reactions and pathways resulting in the breakdown of a monosaccharide (generally glucose) into pyruvate, with the concomitant production of a small amount of ATP. Glycolysis begins with phosphorylation of a monosaccharide (generally glucose) on the sixth carbon by a hexokinase, and ends with the production of pyruvate. Pyruvate may be converted to ethanol, lactate, or other small molecules, or fed into the TCA cycle.
Down:
HK1
Eno1
Pdha1
Aldob
Genes in LSJL involved in Metabolism according to Gene Ontology:
The chemical reactions and pathways, including anabolism and catabolism, by which living organisms transform chemical substances. Metabolic processes typically transform small molecules, but also include macromolecular processes such as DNA repair and replication, and protein synthesis and degradation.
Up:
Ch25h
4933405O20Rik
Sulf1
Slc27a3
Lama4
Agbl2
Gfpt2
Cav3
Down:
Acsl6
Wwox
Aspa
Oxct1
Pecr
Tecta
Atp2a2
Fah
Pdhx
Acsl5
Aldh1a3
Prim2
Idh3g
Ugp2
Partial Gstm6 protein
Chi3l3
Slc6a13
Pdha1
Nat2
Cdyl
Nanp
Pah
Hsdl1
"Prechondrogenic condensation is a critical step for skeletal pattern formation. ATP oscillations play an essential role in prechondrogenic condensation{Maybe LSJL can mimic these ATP oscillations to induce prechondrogenic condensation}. 93 cationic and 109 anionic compounds derived from known metabolic pathways [are involved in chondrogenesis]. 15 cationic and 18 anionic compounds revealed significant change between peak and trough of ATP oscillations. Glycolysis, mitochondrial respiration and uronic acid pathway oscillate in phase with ATP oscillations, while PPRP and nucleotides synthesis pathways oscillate in antiphase with ATP oscillations. ATP-producing glycolysis and mitochondrial respiration oscillate in antiphase with the ATP-consuming PPRP/nucleotide synthesis pathway during chondrogenesis. "
"extracellular ATP and cAMP/PKA signaling mediate ATP oscillations during chondrogenesis"
"ATP oscillations were generated 2–4 d after chondrogenic induction"
"Besides ATP, 3 cationic compounds such as O-acetylcarnitine, phosphorylcholine, and tyramine and 11 anionic compounds such as fructose 1,6-bisphosphate, malate, fumaric acid, 2-oxoglutarate,cis-aconitic acid, 1,3-bisphosphoglycerate, 2-phosphoglycerate, 3-phosphoglycerate, NADH,UDP-glucuronic acid, and glucuronic acid were significantly increased at the peak of PACTIN-PxRe oscillations"<-These compounds likely oscillate along with ATP.
Carnitine related genes upregulated by LSJL:
Down:
Crat
Cpt1b
Choline genes Up:
Lrat
Chrna4
Chrna3
Down:
Cdc2l5
Pafah1b2
Gnb1
Chrna10
Aytl1
Malate genes Up:
Me3
NADH genes Down:
Ndufb8
"glycolysis and TCA cycle oscillate during ATP oscillations."
"glycolytic and mitochondrial oscillations are interdependent on each other."
"NADH oscillates in phase with ATP oscillations."
"oscillatory activity of carnitine O-acetyltransferase may mediate prechondrogenic condensation by modulating cellular proliferation."
"uridine diphosphate (UDP)-glucuronic acid and glucuronic acid were significantly increased in the peak of ATP oscillations. UDP-glucuronic acid is the active form of glucuronic acid for the incorporation of glucuronic acid into chondroitin sulphate. UDP-glucuronic acid is produced from glucose via uronic acid pathway: glucose 6-phosphate is isomerized to glucose 1-phosphate, which then reacts with uridine triphosphate (UTP) to form UDP glucose in a reaction catalyzed by UDP-glucose pyrophosphorylase, and subsequently UDP glucose is oxidized by NAD-dependent UDP-glucose dehydrogenase to yield UDP-glucuronic acid"
"ATP oscillations lead to prechondrogenic condensation by inducing oscillatory secretion of adhesion molecules and ECM involved in cell-cell adhesion"
"Ca2+ influx was shown to mediate ATP oscillations in chondrogenesis"
"12 cationic compounds such as diethanolamine, glycine, guanine, cyclohexylamine, glutamine, aspartic acid, 2-aminoisobutyric acid, methionine sulfoxide, proline, threonine, asparagine, and hydroxyproline and 6 anionic compounds such as phosphoribosylpyrophosphate (PPRP), ADP, dCTP, UDP, GMP, and cGMP were significantly increased in the trough of PACTIN-PxRe oscillations"
Genes in LSJL involved in Glycolysis according to Gene Ontology:
The chemical reactions and pathways resulting in the breakdown of a monosaccharide (generally glucose) into pyruvate, with the concomitant production of a small amount of ATP. Glycolysis begins with phosphorylation of a monosaccharide (generally glucose) on the sixth carbon by a hexokinase, and ends with the production of pyruvate. Pyruvate may be converted to ethanol, lactate, or other small molecules, or fed into the TCA cycle.
Down:
HK1
Eno1
Pdha1
Aldob
Genes in LSJL involved in Metabolism according to Gene Ontology:
The chemical reactions and pathways, including anabolism and catabolism, by which living organisms transform chemical substances. Metabolic processes typically transform small molecules, but also include macromolecular processes such as DNA repair and replication, and protein synthesis and degradation.
Up:
Ch25h
4933405O20Rik
Sulf1
Slc27a3
Lama4
Agbl2
Gfpt2
Cav3
Down:
Acsl6
Wwox
Aspa
Oxct1
Pecr
Tecta
Atp2a2
Fah
Pdhx
Acsl5
Aldh1a3
Prim2
Idh3g
Ugp2
Partial Gstm6 protein
Chi3l3
Slc6a13
Pdha1
Nat2
Cdyl
Nanp
Pah
Hsdl1
KDM2A
Depletion of histone demethylase KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of stem cells from apical papilla.
"The histone demethylase, lysine (K)-specific demethylase 2A (KDM2A), is evolutionarily conserved and ubiquitously expressed members of the JmjC-domain-containing histone demethylase family. KDM2A can regulate the cell proliferation and osteo/dentinogenic differentiation of MSCs. Depletion of KDM2A by short hairpin RNAs can enhance adipogenic and chondrogenic differentiation potentials in human stem cells from apical papilla (SCAPs). Stemness-related genes, SOX2, and the embryonic stem cell master transcription factor, NANOG were significantly increased after silence of KDM2A in SCAPs. Moreover, we found that knock-down of the KDM2A co-factor, BCOR also up-regulated the mRNA levels of SOX2 and NANOG. Silence of KDM2A increased the histone H3 Lysine 4 (H3K4) trimethylation in the SOX2 and NANOG locus and regulates its expression. Depletion of KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of SCAPs by up-regulated SOX2 and NANOG, BCOR is also involved in this regulation as co-factor."
"Five human impacted third molar with immature roots were collected from 3 healthy patients (16–20 years old)"
"the knock-down of BCOR by shRNA prompted the expressions of SOX2 and NANOG in SCAPs"
"The histone demethylase, lysine (K)-specific demethylase 2A (KDM2A), is evolutionarily conserved and ubiquitously expressed members of the JmjC-domain-containing histone demethylase family. KDM2A can regulate the cell proliferation and osteo/dentinogenic differentiation of MSCs. Depletion of KDM2A by short hairpin RNAs can enhance adipogenic and chondrogenic differentiation potentials in human stem cells from apical papilla (SCAPs). Stemness-related genes, SOX2, and the embryonic stem cell master transcription factor, NANOG were significantly increased after silence of KDM2A in SCAPs. Moreover, we found that knock-down of the KDM2A co-factor, BCOR also up-regulated the mRNA levels of SOX2 and NANOG. Silence of KDM2A increased the histone H3 Lysine 4 (H3K4) trimethylation in the SOX2 and NANOG locus and regulates its expression. Depletion of KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of SCAPs by up-regulated SOX2 and NANOG, BCOR is also involved in this regulation as co-factor."
"Five human impacted third molar with immature roots were collected from 3 healthy patients (16–20 years old)"
"the knock-down of BCOR by shRNA prompted the expressions of SOX2 and NANOG in SCAPs"
Saturday, July 18, 2009
HMGB1
HMGB1 is upregulated in the bone marrow with aging. HMGB1 is secreted by hypertrophic chondrocytes.
Hmgb1 can facilitate activation of the matrilin-1 gene promoter by Sox9 and L-Sox5/Sox6 in early steps of chondrogenesis
"The architectural high mobility group box 1 (Hmgb1) protein acts as both a nuclear and an extracellular regulator of various biological processes, including skeletogenesis. Here we report its contribution to the evolutionarily conserved, distinctive regulation of the matrilin-1 gene (Matn1) expression in amniotes. We previously demonstrated that uniquely assembled proximal promoter elements restrict Matn1 expression to specific growth plate cartilage zones by allowing varying doses of L-Sox5/Sox6 and Nfi proteins to fine-tune their Sox9-mediated transactivation. Here, we dissected the regulatory mechanisms underlying the activity of a conserved distal promoter element 1. We show that this element carries three Sox-binding sites, works as an enhancer in vivo, and allows promoter activation by the Sox5/6/9 chondrogenic trio. In early steps of chondrogenesis, declining Hmgb1 expression overlaps with the onset of Sox9 expression. Unlike repression in late steps, Hmgb1 overexpression in early chondrogenesis increases Matn1 promoter activation by the Sox trio, and forced Hmgb1 expression in COS-7 cells facilitates induction of Matn1 expression by the Sox trio. The conserved Matn1 control elements bind Hmgb1 and SOX9 with opposite efficiency in vitro. They show higher HMGB1 than SOX trio occupancy in established chondrogenic cell lines, and HMGB1 silencing greatly increases MATN1 and COL2A1 expression. Together, these data thus suggest a model whereby Hmgb1 helps recruit the Sox trio to the Matn1 promoter and thereby facilitates activation of the gene in early chondrogenesis. We anticipate that Hmgb1 may similarly affect transcription of other cartilage-specific genes."
"Unlike other matrilins, Matn1 is expressed exclusively in cartilage, where it mediates connections between aggrecan, collagen-2 and other molecules. Pericellular Matn1 and Matn3 are needed for Ihh signaling and mechanical stimulation of chondrocyte proliferation and differentiation"
" Dpe1 can directly interact with SOX9 and L-Sox5"
Hmgb1 can facilitate activation of the matrilin-1 gene promoter by Sox9 and L-Sox5/Sox6 in early steps of chondrogenesis
"The architectural high mobility group box 1 (Hmgb1) protein acts as both a nuclear and an extracellular regulator of various biological processes, including skeletogenesis. Here we report its contribution to the evolutionarily conserved, distinctive regulation of the matrilin-1 gene (Matn1) expression in amniotes. We previously demonstrated that uniquely assembled proximal promoter elements restrict Matn1 expression to specific growth plate cartilage zones by allowing varying doses of L-Sox5/Sox6 and Nfi proteins to fine-tune their Sox9-mediated transactivation. Here, we dissected the regulatory mechanisms underlying the activity of a conserved distal promoter element 1. We show that this element carries three Sox-binding sites, works as an enhancer in vivo, and allows promoter activation by the Sox5/6/9 chondrogenic trio. In early steps of chondrogenesis, declining Hmgb1 expression overlaps with the onset of Sox9 expression. Unlike repression in late steps, Hmgb1 overexpression in early chondrogenesis increases Matn1 promoter activation by the Sox trio, and forced Hmgb1 expression in COS-7 cells facilitates induction of Matn1 expression by the Sox trio. The conserved Matn1 control elements bind Hmgb1 and SOX9 with opposite efficiency in vitro. They show higher HMGB1 than SOX trio occupancy in established chondrogenic cell lines, and HMGB1 silencing greatly increases MATN1 and COL2A1 expression. Together, these data thus suggest a model whereby Hmgb1 helps recruit the Sox trio to the Matn1 promoter and thereby facilitates activation of the gene in early chondrogenesis. We anticipate that Hmgb1 may similarly affect transcription of other cartilage-specific genes."
"Unlike other matrilins, Matn1 is expressed exclusively in cartilage, where it mediates connections between aggrecan, collagen-2 and other molecules. Pericellular Matn1 and Matn3 are needed for Ihh signaling and mechanical stimulation of chondrocyte proliferation and differentiation"
" Dpe1 can directly interact with SOX9 and L-Sox5"
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