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 Osteoblast differentiation and skeletal development are regulated by Mdm2–p53 signaling

2006 ◽  
Vol 172 (6) ◽  
pp. 909-921 ◽  
Author(s):  
Christopher J. Lengner ◽  
Heather A. Steinman ◽  
James Gagnon ◽  
Thomas W. Smith ◽  
Janet E. Henderson ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Bone Development ◽  
Skeletal Development ◽  
Critical Role ◽  
Mouse Development ◽  
P53 Signaling ◽  
Absolute Requirement ◽  
Tumorigenic Potential ◽  
Skeletal Defects ◽  
Early Mouse

Mdm2 is required to negatively regulate p53 activity at the peri-implantation stage of early mouse development. However, the absolute requirement for Mdm2 throughout embryogenesis and in organogenesis is unknown. To explore Mdm2–p53 signaling in osteogenesis, Mdm2-conditional mice were bred with Col3.6-Cre–transgenic mice that express Cre recombinase in osteoblast lineage cells. Mdm2-conditional Col3.6-Cre mice die at birth and display multiple skeletal defects. Osteoblast progenitor cells deleted for Mdm2 have elevated p53 activity, reduced proliferation, reduced levels of the master osteoblast transcriptional regulator Runx2, and reduced differentiation. In contrast, p53-null osteoprogenitor cells have increased proliferation, increased expression of Runx2, increased osteoblast maturation, and increased tumorigenic potential, as mice specifically deleted for p53 in osteoblasts develop osteosarcomas. These results demonstrate that p53 plays a critical role in bone organogenesis and homeostasis by negatively regulating bone development and growth and by suppressing bone neoplasia and that Mdm2-mediated inhibition of p53 function is a prerequisite for Runx2 activation, osteoblast differentiation, and proper skeletal formation.

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 STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Siru Zhou ◽  
Qinggang Dai ◽  
Xiangru Huang ◽  
Anting Jin ◽  
Yiling Yang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoblast Differentiation ◽  
Skeletal Development ◽  
Signal Transducer ◽  
Bone Homeostasis ◽  
Loss Of Function ◽  
Skeletal Deformities ◽  
Craniofacial Malformation ◽  
Skeletal Defects ◽  
Transcription 3

AbstractSkeletal deformities are typical AD-HIES manifestations, which are mainly caused by heterozygous and loss-of-function mutations in Signal transducer and activator of transcription 3 (STAT3). However, the mechanism is still unclear and the treatment strategy is limited. Herein, we reported that the mice with Stat3 deletion in osteoblasts, but not in osteoclasts, induced AD-HIES-like skeletal defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture. Mechanistic analyses revealed that STAT3 in cooperation with Msh homeobox 1(MSX1) drove osteoblast differentiation by promoting Distal-less homeobox 5(Dlx5) transcription. Furthermore, pharmacological activation of STAT3 partially rescued skeletal deformities in heterozygous knockout mice, while inhibition of STAT3 aggravated bone loss. Taken together, these data show that STAT3 is critical for modulating skeletal development and maintaining bone homeostasis through STAT3-indcued osteogenesis and suggest it may be a potential target for treatments.

scholarly journals Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

2016 ◽  
Vol 113 (51) ◽  
pp. 14751-14756 ◽  
Author(s):  
Hongchen Cai ◽  
Aimin Liu
Keyword(s):  
Osteoblast Differentiation ◽  
Target Genes ◽  
Skeletal Development ◽  
Ubiquitin Ligase Complex ◽  
Skeletal Defects ◽  
Cullin 3 ◽  
Hh Signaling ◽  
Patched 1 ◽  
Null Mutant Mice

Indian Hedgehog (Ihh) regulates chondrocyte and osteoblast differentiation through the Glioma-associated oncogene homolog (Gli) transcription factors. Previous in vitro studies suggested that Speckle-type POZ protein (Spop), part of the Cullin-3 (Cul3) ubiquitin ligase complex, targets Gli2 and Gli3 for degradation and negatively regulates Hedgehog (Hh) signaling. In this study, we found defects in chondrocyte and osteoblast differentiation inSpop-null mutant mice. Strikingly, both the full-length and repressor forms of Gli3, but not Gli2, were up-regulated inSpopmutants, and Ihh target genesPatched 1(Ptch1) and parathyroid hormone-like peptide (Pthlh) were down-regulated, indicating compromised Hh signaling. Consistent with this finding, reducing Gli3 dosage greatly rescued theSpopmutant skeletal defects. We further show that Spop directly targets the Gli3 repressor for ubiquitination and degradation. Finally, we demonstrate in a conditional mutant that loss ofSpopresults in brachydactyly and osteopenia, which can be rescued by reducing the dosage of Gli3. In summary, Spop is an important positive regulator of Ihh signaling and skeletal development.

scholarly journals Wdr5, a WD-40 protein, regulates osteoblast differentiation during embryonic bone development

2006 ◽  
Vol 295 (2) ◽  
pp. 498-506 ◽  
Author(s):  
Francesca Gori ◽  
Lauren G. Friedman ◽  
Marie B. Demay
Keyword(s):  
Osteoblast Differentiation ◽  
Bone Development ◽  
Embryonic Bone

scholarly journals Microarray Analyses of Gene Expression during Chondrocyte Differentiation Identifies Novel Regulators of Hypertrophy

2005 ◽  
Vol 16 (11) ◽  
pp. 5316-5333 ◽  
Author(s):  
Claudine G. James ◽  
C. Thomas G. Appleton ◽  
Veronica Ulici ◽  
T. Michael Underhill ◽  
Frank Beier
Keyword(s):  
Gene Expression ◽  
Bone Development ◽  
Skeletal Development ◽  
Expression Patterns ◽  
Chondrocyte Differentiation ◽  
Endochondral Bone ◽  
Temporal Gene Expression ◽  
Affymetrix Microarrays ◽  
Time Period ◽  
And Cluster Analysis

Ordered chondrocyte differentiation and maturation is required for normal skeletal development, but the intracellular pathways regulating this process remain largely unclear. We used Affymetrix microarrays to examine temporal gene expression patterns during chondrogenic differentiation in a mouse micromass culture system. Robust normalization of the data identified 3300 differentially expressed probe sets, which corresponds to 1772, 481, and 249 probe sets exhibiting minimum 2-, 5-, and 10-fold changes over the time period, respectively. GeneOntology annotations for molecular function show changes in the expression of molecules involved in transcriptional regulation and signal transduction among others. The expression of identified markers was confirmed by RT-PCR, and cluster analysis revealed groups of coexpressed transcripts. One gene that was up-regulated at later stages of chondrocyte differentiation was Rgs2. Overexpression of Rgs2 in the chondrogenic cell line ATDC5 resulted in accelerated hypertrophic differentiation, thus providing functional validation of microarray data. Collectively, these analyses provide novel information on the temporal expression of molecules regulating endochondral bone development.

scholarly journals The influence of a high-protein, low-carbohydrate diet on bone development in the fetuses of rat dams with streptozotocin-induced diabetes

1988 ◽  
Vol 59 (1) ◽  
pp. 57-62 ◽  
Author(s):  
W. Keith Harvey ◽  
Tetsuo Nakamoto
Keyword(s):  
G Protein ◽  
Collagen Synthesis ◽  
Bone Development ◽  
High Protein ◽  
Diabetic Group ◽  
Long Bones ◽  
Carbohydrate Diet ◽  
Low Carbohydrate Diet ◽  
Low Carbohydrate ◽  
Ca Uptake

1. The purpose of the present study was to determine the effects of diet on the mandibles and growth centres of the long bones in the fetuses of diabetic rat dams given a normal diet compared with those given a high-protein, low-carbohydrate diet.2. On the 9th day of gestation, the controls, groups 1 and 3, were injected with citrate buffer and given 200 and 600 g protein/kg diets respectively. Groups 2 and 4 were injected with 40 mg streptozotocin/kg body-weight and pair-fed with groups I and 3 respectively on the 200 and 600 g protein/kg diets.3. On day 22, some dams were injected with either 45Ca or [14C]proline. Mandibles and long bones were removed and weighed and analysed for Ca content, 45Ca uptake, collagen and collagen synthesis.4. The body-weights, and mandibular and long-bone weights of the fetuses in the diabetic 200 g protein/kg group were smaller than those of the non-diabetic 200 g protein/kg group, whereas those of the diabetic 600 g protein/kg group showed no difference from the non-diabetic 600 g protein/kg group.5. The rate of collagen synthesis was higher in the fetuses of the diabetic 600 g protein/kg group than those of the non-diabetic group. Bones of the diabetic 200 g protein/kg group were lower in collagen content when compared with the non-diabetic group, whereas there was no difference between the diabetic and non-diabetic 600 g protein/kg groups.6. Ca uptake and total Ca contents in the mandibles and long bones showed no difference between diabetic and non-diabetic groups fed on both diets.7. A high-protein, low-carbohydrate diet appeared to have a certain beneficial effect on bone development of the growing fetuses from diabetic dams.

scholarly journals A Case of Rhizomelic Chondrodysplasia Punctata in Newborn

2014 ◽  
Vol 2014 ◽  
pp. 1-3 ◽  
Author(s):  
Nalan Karabayır ◽  
Gonca Keskindemirci ◽  
Erdal Adal ◽  
Orhan Korkmaz
Keyword(s):  
Soft Tissues ◽  
Clinical Symptoms ◽  
Current Knowledge ◽  
Chondrodysplasia Punctata ◽  
Long Bones ◽  
Rhizomelic Chondrodysplasia Punctata ◽  
Cervical Spinal Stenosis ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Severe Growth

Rhizomelic chondrodysplasia punctate (RCDP) is a rare autosomal recessive peroxisomal disease. The main features of the disease are shortening of the proximal long bones, punctate calcifications located in the epiphyses of long bones and in soft tissues around joints and vertebral column, vertebral clefting, dysmorphic face, and severe growth retardation, whereas cervical spinal stenosis may also rarely be present. Imaging of the brain and spinal cord in patients with this disorder may aid prognosis and guide management decisions. We report the newborn diagnosed as CDP with cervical stenosis. Our aim is to discuss current knowledge on etiopathogenesis as well as radiological and clinical symptoms of diseases associated with CDP.

scholarly journals SLC1A5 provides glutamine and asparagine necessary for bone development in mice

2021 ◽  
Author(s):  
Deepika Sharma ◽  
Yilin Yu ◽  
Leyao Shen ◽  
Guo-Fang Zhang ◽  
Courtney M. Karner
Keyword(s):  
Amino Acid ◽  
Osteoblast Differentiation ◽  
Bone Development ◽  
Essential Amino Acids ◽  
Amino Acid Production ◽  
Matrix Synthesis ◽  
Acid Biosynthesis ◽  
Intracellular Amino Acid ◽  
Metabolomic Approach ◽  
Asparagine Metabolism

Osteoblast differentiation is sequentially characterized by high rates of proliferation followed by increased protein and matrix synthesis, processes that require substantial amino acid acquisition and production. How osteoblasts obtain or maintain intracellular amino acid production is poorly understood. Here we identify Slc1a5 as a critical amino acid transporter during bone development. Using a genetic and metabolomic approach, we show Slc1a5 acts cell autonomously in osteoblasts to import glutamine and asparagine. Deleting Slc1a5 or reducing either glutamine or asparagine availability prevents protein synthesis and osteoblast differentiation. Mechanistically, glutamine and asparagine metabolism support amino acid biosynthesis. Thus, osteoblasts depend on Slc1a5 to provide glutamine and asparagine, which are subsequently used to produce non-essential amino acids and support osteoblast differentiation and bone development.

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