Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Wilfredo Molina

Keyword(s):

Bone Formation ◽

Human Fetus ◽

Mandibular Condyle ◽

Endochondral Bone Formation ◽

Endochondral Bone ◽

Histological Changes ◽

Histological Sections ◽

Early Stages ◽

Mesenchymal Tissue ◽

Periodic Reaction

Histochemical studies on the mandibular condyle of the human fetus at gestational ages 12, 14, and 16 weeks were performed. Methods. Histological sections were stained with Schiff’s periodic reaction for glicoproteins, hematoxiline eosine detects mesenchymal tissue and trichhromic stain for collagen. The ANOVA one-way test was used to evaluate the differences during stained zones in the three fetus groups. Results. The percentage of glycoproteins and mesenchymal tissue was denser at 12 weeks. This percentage decreases at 14 weeks and is less at 16 weeks. An increase in the amount of collagen in the studied weeks was observed. The percentages of glycoproteins, mesenchymal tissue, and collagen were significantly different; f = 4373, 9624.8, and 3674, P<0.0001 for the three studied groups. Conclusion. The endochondral bone formation of the mandibular condyle includes modifications of the quantities of glycoproteins, mesenchymal tissue, and collagen.

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Selective Deficiency of the “Bone-related”Runx2-II Unexpectedly Preserves Osteoblast-mediated Skeletogenesis

Journal of Biological Chemistry ◽

10.1074/jbc.m401109200 ◽

2004 ◽

Vol 279 (19) ◽

pp. 20307-20313 ◽

Cited By ~ 66

Author(s):

Zhou-Sheng Xiao ◽

Anita B. Hjelmeland ◽

L. D. Quarles

Keyword(s):

Bone Formation ◽

Ex Vivo ◽

Mesenchymal Cells ◽

Endochondral Bone Formation ◽

Endochondral Bone ◽

Chondrocyte Maturation ◽

Intramembranous Bone ◽

Exon 1 ◽

Metaphyseal Bone ◽

Deficient Mice

Runx2 (runt-related transcription factor 2) is a master regulator of skeletogenesis. Distinct promoters in the Runx2 gene transcribe the “bone-related”Runx2-II and non-osseousRunx2-I isoforms that differ only in their respective N termini. Existing mutant mouse models with both isoforms deleted exhibit an arrest of osteoblast and chondrocyte maturation and the complete absence of mineralized bone, but they do not distinguish the separate functions of the two N-terminal isoforms. To elucidate the function of the bone-related isoform, we generated selectiveRunx2-II-deficient mice by the targeted deletion of the distal promoter and exon 1. HomozygousRunx2-II-deficient (Runx2-II-/-) mice unexpectedly formed axial, appendicular, and craniofacial bones derived from either intramembranous ossification or mesenchymal cells of the bone collar, but they failed to form the posterior cranium and other bones derived from endochondral ossification. HeterozygousRunx2-II-deficient mice had grossly normal skeletons, but were osteopenic. The commitment of mesenchymal cellsex vivoto the osteoblast lineage occurred inRunx2-II-/-mice, but osteoblastic gene expression was impaired. Chondrocyte maturation appeared normal, but the zone of hypertrophic chondrocytes was not transformed into metaphyseal bone, leading to widened growth plates inRunx2-II-/-mice. Compensatory increments inRunx2-I expression occurred inRunx2-II-/-mice but were not sufficient to normalize osteoblastic maturation or transcriptional activity. Our findings support distinct functions ofRunx2-II and -I in the control of skeletogenesis.Runx2-I is sufficient for early osteoblastogenesis and intramembranous bone formation, whereasRunx2-II is necessary for complete osteoblastic maturation and endochondral bone formation.

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Faculty Opinions recommendation of Intraflagellar transport is essential for endochondral bone formation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1059698.511609 ◽

2007 ◽

Author(s):

Peter Scambler

Keyword(s):

Bone Formation ◽

Intraflagellar Transport ◽

Endochondral Bone Formation ◽

Endochondral Bone

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The culture microenvironment of juvenile idiopathic arthritis synovial fibroblasts is favorable for endochondral bone formation through BMP4 and repressed by chondrocytes

Pediatric Rheumatology ◽

10.1186/s12969-021-00556-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Megan M. Simonds ◽

Amanda R. Schlefman ◽

Suzanne M. McCahan ◽

Kathleen E. Sullivan ◽

Carlos D. Rose ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Bone Formation ◽

Synovial Fibroblasts ◽

Conditioned Media ◽

Endochondral Bone Formation ◽

Endochondral Bone ◽

Member Gene ◽

Bmp Antagonist ◽

Fibroblast Like Synoviocytes ◽

Tgfβ Superfamily

Abstract Background We examined influences of conditioned media from chondrocytes (Ch) on juvenile idiopathic arthritis synovial fibroblasts (JFLS) and potential for JFLS to undergo endochondral bone formation (EBF). Methods Primary cells from three control fibroblast-like synoviocytes (CFLS) and three JFLS were cultured in Ch-conditioned media and compared with untreated fibroblast-like synoviocytes (FLS). RNA was analyzed by ClariomS microarray. FLS cells cultured in conditioned media were exposed to either TGFBR1 inhibitor LY3200882 or exogenous BMP4 and compared with FLS cultured in conditioned media from Ch (JFLS-Ch). Media supernatants were analyzed by ELISA. Results In culture, JFLS downregulate BMP2 and its receptor BMPR1a while upregulating BMP antagonists (NOG and CHRD) and express genes (MMP9, PCNA, MMP12) and proteins (COL2, COLX, COMP) associated with chondrocytes. Important TGFβ superfamily member gene expression (TGFBI, MMP9, COL1A1, SOX6, and MMP2) is downregulated when JFLS are cultured in Ch-conditioned media. COL2, COLX and COMP protein expression decreases in JFLS-Ch. BMP antagonist protein (NOG, CHRD, GREM, and FST) secretion is significantly increased in JFLS-Ch. Protein phosphorylation increases in JFLS-Ch exposed to exogenous BMP4, and chondrocyte-like phenotype is restored in BMP4 presence, evidenced by increased secretion of COL2 and COLX. Inhibition of TGFBR1 in JFLS-Ch results in overexpression of COL2. Conclusions JFLS are chondrocyte-like, and Ch-conditioned media can abrogate this phenotype. The addition of exogenous BMP4 causes JFLS-Ch to restore this chondrocyte-like phenotype, suggesting that JFLS create a microenvironment favorable for endochondral bone formation, thereby contributing to joint growth disturbances in juvenile idiopathic arthritis.

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Intraflagellar transport is essential for endochondral bone formation

Development ◽

10.1242/dev.02732 ◽

2007 ◽

Vol 134 (2) ◽

pp. 307-316 ◽

Cited By ~ 238

Author(s):

C. J. Haycraft ◽

Q. Zhang ◽

B. Song ◽

W. S. Jackson ◽

P. J. Detloff ◽

...

Keyword(s):

Bone Formation ◽

Intraflagellar Transport ◽

Endochondral Bone Formation ◽

Endochondral Bone

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Osteoblast‐Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing

Journal of Bone and Mineral Research ◽

10.1002/jbmr.2510 ◽

2015 ◽

Vol 30 (9) ◽

pp. 1572-1584 ◽

Cited By ~ 32

Author(s):

Tao Wang ◽

Yongmei Wang ◽

Alicia Menendez ◽

Chak Fong ◽

Muriel Babey ◽

...

Keyword(s):

Bone Formation ◽

Fracture Healing ◽

Endochondral Bone Formation ◽

Endochondral Bone ◽

Specific Loss ◽

Igf1r Signaling

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Conditional Deletion of Prolyl Hydroxylase Domain-Containing Protein 2 (Phd2) Gene Reveals Its Essential Role in Chondrocyte Function and Endochondral Bone Formation

Endocrinology ◽

10.1210/en.2015-1473 ◽

2016 ◽

Vol 157 (1) ◽

pp. 127-140 ◽

Cited By ~ 11

Author(s):

Shaohong Cheng ◽

Weirong Xing ◽

Sheila Pourteymoor ◽

Jan Schulte ◽

Subburaman Mohan

Keyword(s):

Bone Formation ◽

Growth Plate ◽

Prolyl Hydroxylase ◽

Conditional Knockout ◽

Hypertrophic Chondrocytes ◽

Endochondral Bone Formation ◽

Bone Surface ◽

Endochondral Bone ◽

Prolyl Hydroxylase Domain

Abstract The hypoxic growth plate cartilage requires hypoxia-inducible factor (HIF)-mediated pathways to maintain chondrocyte survival and differentiation. HIF proteins are tightly regulated by prolyl hydroxylase domain-containing protein 2 (Phd2)-mediated proteosomal degradation. We conditionally disrupted the Phd2 gene in chondrocytes by crossing Phd2 floxed mice with type 2 collagen-α1-Cre transgenic mice and found massive increases (>50%) in the trabecular bone mass of long bones and lumbar vertebra of the Phd2 conditional knockout (cKO) mice caused by significant increases in trabecular number and thickness and reductions in trabecular separation. Cortical thickness and tissue mineral density at the femoral middiaphysis of the cKO mice were also significantly increased. Dynamic histomorphometric analyses revealed increased longitudinal length and osteoid surface per bone surface in the primary spongiosa of the cKO mice, suggesting elevated conversion rate from hypertrophic chondrocytes to mineralized bone matrix as well as increased bone formation in the primary spongiosa. In the secondary spongiosa, bone formation measured by mineralizing surface per bone surface and mineral apposition rate were not changed, but resorption was slightly reduced. Increases in the mRNA levels of SRY (sex determining region Y)-box 9, osterix (Osx), type 2 collagen, aggrecan, alkaline phosphatase, bone sialoprotein, vascular endothelial growth factor, erythropoietin, and glycolytic enzymes in the growth plate of cKO mice were detected by quantitative RT-PCR. Immunohistochemistry revealed an increased HIF-1α protein level in the hypertrophic chondrocytes of cKO mice. Infection of chondrocytes isolated from Phd2 floxed mice with adenoviral Cre resulted in similar gene expression patterns as observed in the cKO growth plate chondrocytes. Our findings indicate that Phd2 suppresses endochondral bone formation, in part, via HIF-dependent mechanisms in mice.

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