scholarly journals Intestinal cell kinase regulates chondrocyte proliferation and maturation during skeletal development

2017 ◽  
Author(s):  
Mengmeng Ding ◽  
Li Jin ◽  
Lin Xie ◽  
So Hyun Park ◽  
Yixin Tong ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Molecular Mechanisms ◽  
Skeletal Development ◽  
Spinal Column ◽  
Intestinal Cell ◽  
Long Bones ◽  
Chondrocyte Proliferation ◽  
Kinase Gene ◽  
Skeletal Defects ◽  
Intestinal Cell Kinase

AbstractAn autosomal recessive loss-of-function mutation R272Q in human ICK (intestinal cell kinase) gene causes profound multiplex developmental defects in human ECO (endocrine-cerebro-osteodysplasia) syndrome. ECO patients exhibit a wide variety of skeletal abnormalities, yet the underlying cellular and molecular mechanisms by which ICK regulates skeletal development remain largely unknown. The goal of this study is to understand the structural and mechanistic basis underlying skeletal anomalies caused by ICK dysfunction. Ick R272Q knock in transgenic mouse model not only recapitulated major ECO skeletal defects such as short limbs and polydactyly but also revealed a deformed spine with deficient intervertebral disc. Loss of ICK functions markedly reduces mineralization in the spinal column, ribs, and long bones. Ick mutants show a significant decrease in the number of proliferating chondrocytes and type X collagen-expressing hypertrophic chondrocytes in the spinal column and the growth plate of long bones. Our results demonstrate that ICK plays an important role in bone and intervertebral disc development by promoting chondrocyte proliferation and maturation, and thus provide novel mechanistic insights into the skeletal phenotypes of human ECO syndrome.

scholarly journals A Murine Model for Human ECO Syndrome Reveals a Critical Role of Intestinal Cell Kinase in Skeletal Development

2017 ◽  
Vol 102 (3) ◽  
pp. 348-357 ◽  
Author(s):  
Mengmeng Ding ◽  
Li Jin ◽  
Lin Xie ◽  
So Hyun Park ◽  
Yixin Tong ◽  
...  
Keyword(s):  
Murine Model ◽  
Skeletal Development ◽  
Critical Role ◽  
Intestinal Cell ◽  
Intestinal Cell Kinase

scholarly journals Stat3 loss in mesenchymal progenitors causes Job syndrome–like skeletal defects by reducing Wnt/β-catenin signaling

2021 ◽  
Vol 118 (26) ◽  
pp. e2020100118
Author(s):  
Prem Swaroop Yadav ◽  
Shuhao Feng ◽  
Qian Cong ◽  
Hanjun Kim ◽  
Yuchen Liu ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Clinical Symptoms ◽  
Bone Development ◽  
Skeletal Development ◽  
Genetic Disorder ◽  
Long Bones ◽  
Multiple Fractures ◽  
Osteoprogenitor Cells ◽  
Skeletal Defects ◽  
Job Syndrome

Job syndrome is a rare genetic disorder caused by STAT3 mutations and primarily characterized by immune dysfunction along with comorbid skeleton developmental abnormalities including osteopenia, recurrent fracture of long bones, and scoliosis. So far, there is no definitive cure for the skeletal defects in Job syndrome, and treatments are limited to management of clinical symptoms only. Here, we have investigated the molecular mechanism whereby Stat3 regulates skeletal development and osteoblast differentiation. We showed that removing Stat3 function in the developing limb mesenchyme or osteoprogenitor cells in mice resulted in shortened and bow limbs with multiple fractures in long bones that resembled the skeleton symptoms in the Job Syndrome. However, Stat3 loss did not alter chondrocyte differentiation and hypertrophy in embryonic development, while osteoblast differentiation was severely reduced. Genome-wide transcriptome analyses as well as biochemical and histological studies showed that Stat3 loss resulted in down-regulation of Wnt/β-catenin signaling. Restoration of Wnt/β-catenin signaling by injecting BIO, a small molecule inhibitor of GSK3, or crossing with a Lrp5 gain of function (GOF) allele, rescued the bone reduction phenotypes due to Stat3 loss to a great extent. These studies uncover the essential functions of Stat3 in maintaining Wnt/β-catenin signaling in early mesenchymal or osteoprogenitor cells and provide evidence that bone defects in the Job Syndrome are likely caused by Wnt/β-catenin signaling reduction due to reduced STAT3 activities in bone development. Enhancing Wnt/β-catenin signaling could be a therapeutic approach to reduce bone symptoms of Job syndrome patients.

scholarly journals Osteopotentia regulates osteoblast maturation, bone formation, and skeletal integrity in mice

2010 ◽  
Vol 189 (3) ◽  
pp. 511-525 ◽  
Author(s):  
Michael L. Sohaskey ◽  
Yebin Jiang ◽  
Jenny J. Zhao ◽  
Andreas Mohr ◽  
Frank Roemer ◽  
...  
Keyword(s):  
Bone Formation ◽  
Matrix Protein ◽  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Skeletal Development ◽  
Control Point ◽  
Type I ◽  
Osteoblast Function ◽  
Skeletal Defects ◽  
Osteoblast Maturation

During skeletal development and regeneration, bone-forming osteoblasts respond to high metabolic demand by active expansion of their rough endoplasmic reticulum (rER) and increased synthesis of type I collagen, the predominant bone matrix protein. However, the molecular mechanisms that orchestrate this response are not well understood. We show that insertional mutagenesis of the previously uncharacterized osteopotentia (Opt) gene disrupts osteoblast function and causes catastrophic defects in postnatal skeletal development. Opt encodes a widely expressed rER-localized integral membrane protein containing a conserved SUN (Sad1/Unc-84 homology) domain. Mice lacking Opt develop acute onset skeletal defects that include impaired bone formation and spontaneous fractures. These defects result in part from a cell-autonomous failure of osteoblast maturation and a posttranscriptional decline in type I collagen synthesis, which is concordant with minimal rER expansion. By identifying Opt as a crucial regulator of bone formation in the mouse, our results uncover a novel rER-mediated control point in osteoblast function and implicate human Opt as a candidate gene for brittle bone disorders.

Melatonin: Protection of the Intervertebral Disc

2019 ◽  
Vol 2 (3) ◽  
pp. 1-9
Author(s):  
Russel J Reiter ◽  
Sergio Rosales-Corral ◽  
Ramaswamy Sharma
Keyword(s):  
Intervertebral Disc ◽  
Molecular Mechanisms ◽  
Intervertebral Discs ◽  
Lumbar Pain ◽  
Low Back ◽  
Work Time ◽  
Protective Actions ◽  
Aging Populations ◽  
Definition Of ◽  
Endogenous Melatonin

     Low back pain (lumbar pain) due to injury of or damage to intervertebral discs is common in all societies.  The loss of work time as a result of this problem is massive.  Recent research suggests that melatonin may prevent or counteract intervertebral disc damage. This may be especially relevant in aging populations given that endogenous melatonin, in most individuals, dwindles with increasing age. The publications related to melatonin and its protection of the intervertebral disc are reviewed herein, including definition of some molecular mechanisms that account for melatonin’s protective actions. 

Therapeutic Application of Diacylglycerol Oil for Obesity: Serotonin Hypothesis

2012 ◽  
Vol 2 (1) ◽  
pp. 1 ◽  
Author(s):  
Hidekatsu Yanai ◽  
Hiroshi Yoshida ◽  
Yuji Hirowatari ◽  
Norio Tada
Keyword(s):  
Energy Expenditure ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serotonin Release ◽  
Intestinal Cell ◽  
Therapeutic Application ◽  
Postprandial Triglyceride

Characteristics for the serum lipid abnormalities in the obesity/metabolic syndrome are elevated fasting, postprandial triglyceride (TG), and decreased high-density lipoprotein-cholesterol (HDL-C). Diacylglycerol (DAG) oil ingestion has been reported to ameliorate postprandial hyperlipidemia and prevent obesity by increasing energy expenditure, due to the intestinal physiochemical dynamics that differ from triacylglycerol (TAG). Our study demonstrated that DAG suppresses postprandial increase in TG-rich lipoprotein, very low-density lipoprotein (VLDL), and insulin, as compared with TAG in young, healthy individuals. Interestingly, our study also presented that DAG significantly increases plasma serotonin, which is mostly present in the intestine, and mediates thermogenesis, proposing a possible mechanism for a postprandial increase in energy expenditure by DAG. Our other study demonstrated that DAG suppresses postprandial increase in TG, VLDL-C, and remnant-like particle-cholesterol, in comparison with TAG in an apolipoprotein C-II deficient subject, suggesting that DAG suppresses postprandial TG-rich lipoprotein independently of lipoprotein lipase. Further, to understand the molecular mechanisms for DAG-mediated increase in serotonin and energy expenditure, we studied the effects of 1-monoacylglycerol and 2-monoacylglycerol, distinct digestive products of DAG and TAG, respectively, on serotonin release from the Caco-2 cells, the human intestinal cell line. We also studied effects of 1- and 2-monoacylglycerol, and serotonin on the expression of mRNA associated with β-oxidation, fatty acids metabolism, and thermogenesis, in the Caco-2 cells. 1-monoacylglycerol significantly increased serotonin release from the Caco-2 cells, compared with 2-monoacylglycerol by approximately 40%. The expression of mRNA of acyl-CoA oxidase (ACO), fatty acid translocase (FAT), and uncoupling protein-2 (UCP-2), was significantly higher in 1-MOG-treated Caco-2 cells, than 2-MOG-treated cells. The expression of mRNA of ACO, medium-chain acyl-CoA dehydrogenase, FAT, and UCP-2, was significantly elevated in serotonin-treated Caco-2 cells, compared to cells incubated without serotonin. In conclusion, our clinical and in vitro studies suggested a possible therapeutic application of DAG for obesity, and obesity-related metabolic disorders.Key words: Diacylglycerol, intestine, obesity, serotonin, thermogenesis

scholarly journals Ultrastructural and molecular analysis of the origin and differentiation of cells mediating brittle star skeletal regeneration

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Laura Piovani ◽  
Anna Czarkwiani ◽  
Cinzia Ferrario ◽  
Michela Sugni ◽  
Paola Oliveri
Keyword(s):  
Molecular Mechanisms ◽  
Close Contact ◽  
Skeletal Development ◽  
Morphological Differentiation ◽  
Brittle Star ◽  
Marker Genes ◽  
Body Parts ◽  
Coelomic Cavity ◽  
Expression Of Genes ◽  
Skeletal Regeneration

Abstract Background Regeneration is the ability to re-grow body parts or tissues after trauma, and it is widespread across metazoans. Cells involved in regeneration can arise from a pool of undifferentiated proliferative cells or be recruited from pre-existing differentiated tissues. Both mechanisms have been described in different phyla; however, the cellular and molecular mechanisms employed by different animals to restore lost tissues as well as the source of cells involved in regeneration remain largely unknown. Echinoderms are a clade of deuterostome invertebrates that show striking larval and adult regenerative abilities in all extant classes. Here, we use the brittle star Amphiura filiformis to investigate the origin and differentiation of cells involved in skeletal regeneration using a combination of microscopy techniques and molecular markers. Results Our ultrastructural analyses at different regenerative stages identify a population of morphologically undifferentiated cells which appear in close contact with the proliferating epithelium of the regenerating aboral coelomic cavity. These cells express skeletogenic marker genes, such as the transcription factor alx1 and the differentiation genes c-lectin and msp130L, and display a gradient of morphological differentiation from the aboral coelomic cavity towards the epidermis. Cells closer to the epidermis, which are in contact with developing spicules, have the morphology of mature skeletal cells (sclerocytes), and express several skeletogenic transcription factors and differentiation genes. Moreover, as regeneration progresses, sclerocytes show a different combinatorial expression of genes in various skeletal elements. Conclusions We hypothesize that sclerocyte precursors originate from the epithelium of the proliferating aboral coelomic cavity. As these cells migrate towards the epidermis, they differentiate and start secreting spicules. Moreover, our study shows that molecular and cellular processes involved in skeletal regeneration resemble those used during skeletal development, hinting at a possible conservation of developmental programmes during adult regeneration. Finally, we highlight that many genes involved in echinoderm skeletogenesis also play a role in vertebrate skeleton formation, suggesting a possible common origin of the deuterostome endoskeleton pathway.

scholarly journals Expression of Phosphocitrate-Targeted Genes in Osteoarthritis Menisci

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Yubo Sun ◽  
David R. Mauerhan ◽  
Nury M. Steuerwald ◽  
Jane Ingram ◽  
Jeffrey S. Kneisl ◽  
...  
Keyword(s):  
Immune System ◽  
Molecular Mechanisms ◽  
Fibroblast Growth Factor Receptor ◽  
Collagen Type ◽  
Skeletal Development ◽  
Growth Factor Receptor ◽  
Type Ii ◽  
Immune System Activation ◽  
System Activation ◽  
Disease Modifying

Phosphocitrate (PC) inhibited calcium crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the molecular mechanisms remain elusive. This study sought to determine PC targeted genes and the expression of select PC targeted genes in OA menisci to test hypothesis that PC exerts its disease modifying activity in part by reversing abnormal expressions of genes involved in OA. We found that PC downregulated the expression of numerous genes classified in immune response, inflammatory response, and angiogenesis, including chemokine (C-C motif) ligand 5, Fc fragment of IgG, low affinity IIIb receptor (FCGR3B), and leukocyte immunoglobulin-like receptor, subfamily B member 3 (LILRB3). In contrast, PC upregulated the expression of many genes classified in skeletal development, including collagen type II alpha1, fibroblast growth factor receptor 3 (FGFR3), and SRY- (sex determining region Y-) box 9 (SOX-9). Immunohistochemical examinations revealed higher levels of FCGR3B and LILRB3 and lower level of SOX-9 in OA menisci. These findings indicate that OA is a disease associated with immune system activation and decreased expression of SOX-9 gene in OA menisci. PC exerts its disease modifying activity on OA, at least in part, by targeting immune system activation and the production of extracellular matrix and selecting chondroprotective proteins.

scholarly journals Oscillatory Ca2+ Signaling in the Isolated Caenorhabditis elegans Intestine

2005 ◽  
Vol 126 (4) ◽  
pp. 379-392 ◽  
Author(s):  
Maria V. Espelt ◽  
Ana Y. Estevez ◽  
Xiaoyan Yin ◽  
Kevin Strange
Keyword(s):  
Caenorhabditis Elegans ◽  
Intestinal Epithelium ◽  
Oscillation Frequency ◽  
Gene Networks ◽  
Molecular Mechanisms ◽  
Apical Cell ◽  
Intestinal Cell ◽  
C Elegans ◽  
Contrast Gain ◽  
Behavioral Rhythm

Defecation in the nematode Caenorhabditis elegans is a readily observable ultradian behavioral rhythm that occurs once every 45–50 s and is mediated in part by posterior body wall muscle contraction (pBoc). pBoc is not regulated by neural input but instead is likely controlled by rhythmic Ca2+ oscillations in the intestinal epithelium. We developed an isolated nematode intestine preparation that allows combined physiological, genetic, and molecular characterization of oscillatory Ca2+ signaling. Isolated intestines loaded with fluo-4 AM exhibit spontaneous rhythmic Ca2+ oscillations with a period of ∼50 s. Oscillations were only detected in the apical cell pole of the intestinal epithelium and occur as a posterior-to-anterior moving intercellular Ca2+ wave. Loss-of-function mutations in the inositol-1,4,5-trisphosphate (IP3) receptor ITR-1 reduce pBoc and Ca2+ oscillation frequency and intercellular Ca2+ wave velocity. In contrast, gain-of-function mutations in the IP3 binding and regulatory domains of ITR-1 have no effect on pBoc or Ca2+ oscillation frequency but dramatically increase the speed of the intercellular Ca2+ wave. Systemic RNA interference (RNAi) screening of the six C. elegans phospholipase C (PLC)–encoding genes demonstrated that pBoc and Ca2+ oscillations require the combined function of PLC-γ and PLC-β homologues. Disruption of PLC-γ and PLC-β activity by mutation or RNAi induced arrhythmia in pBoc and intestinal Ca2+ oscillations. The function of the two enzymes is additive. Epistasis analysis suggests that PLC-γ functions primarily to generate IP3 that controls ITR-1 activity. In contrast, IP3 generated by PLC-β appears to play little or no direct role in ITR-1 regulation. PLC-β may function instead to control PIP2 levels and/or G protein signaling events. Our findings provide new insights into intestinal cell Ca2+ signaling mechanisms and establish C. elegans as a powerful model system for defining the gene networks and molecular mechanisms that underlie the generation and regulation of Ca2+ oscillations and intercellular Ca2+ waves in nonexcitable cells.

Characterization of an A-type cyclin-dependent kinase gene from Dendrobium candidum

Biologia ◽  
2012 ◽  
Vol 67 (2) ◽  
Author(s):  
Gang Zhang ◽  
Chao Song ◽  
Ming-Ming Zhao ◽  
Biao Li ◽  
Shun-Xing Guo
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Postembryonic Development ◽  
Kinase Domain ◽  
Dimensional Structure ◽  
Pcr Analysis ◽  
Kinase Gene ◽  
Multiple Sequence ◽  
Dendrobium Candidum ◽  
Rapid Amplification

AbstractCyclin-dependent kinases (CDKs) play an essential role in cell cycle regulation during the embryonic and postembryonic development of organisms. To better understand the molecular mechanisms of CDKs involved in embryogenesis regulation in the endangered medicinal plant Dendrobium candidum Wall. ex Lindl., a 1229-bp full-length cDNA of an A-type CDK gene, Denca;CDKA;1, was identified using 3′ rapid amplification of cDNA end (RACE) PCR. Denca;CDKA;1 was predicted to encode a 294 amino acid residue-long protein of 33.76 kDa with an isoelectric point of 7.72. The deduced Denca;CDKA;1 protein contained a conserved serine/threonine-protein kinase domain (S-TKc) and a canonical cyclinbinding “PSTAIRE” motif. Multiple sequence alignment indicated that members of CDKA family from various plants exhibited a high degree of sequence identity ranging from 82% to 93%. A neighbor-joining phylogenetic tree showed that Denca;CDKA;1 was clustered into the plant group and was distant from the animal and fungal groups. The modeled three-dimensional structure of Denca;CDKA;1 exhibited the similar functional structure of a fold consisting of β-sheets and α-helices joined by discontinuous random coils forming two relatively independent lobes. Quantitative real-time PCR analysis revealed that Denca;CDKA;1 transcripts were the most abundant in protocorm-like bodies with 4.76 fold, followed by that in roots (4.19 fold), seeds (2.57 fold), and stems (1.57 fold). This study characterized the novel Denca;CDKA;1 gene from D. candidum for the first time and the results will be useful for further functional determination of the gene.

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