Coordination of chondrocyte differentiation and joint formation byα5β1 integrin in the developing appendicular skeleton

Garciadiego-Cázares, David; Rosales, Carlos; Katoh, Masaru; Chimal‐Monroy, Jesús

doi:10.1242/dev.01345

Cited by 96 publications

(86 citation statements)

References 38 publications

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“…Several previous studies have indicated an inductive role of ␤1 integrins in hypertrophic differentiation. Signaling via ␣1␤1 and ␣5␤1 integrins was required for hypertrophy of cultured AC chondrocytes induced by transglutaminases (33,34), ␤1 integrin-blocking antibody impaired chondrocyte hypertrophy and collagen X deposition in sternal organ culture (35), and misexpression of ␣5␤1 integrin in embryonic chick legs resulted in joint fusion and initiation of the hypertrophic differentiation program (13). Finally, we have demonstrated that hypertrophic differentiation is delayed in ␤1 fl/fl -Prx1cre ؉ mice.…”

Section: Discussionmentioning

confidence: 68%

“…In the embryonic mouse limb culture system, administration of ␤1 and ␣5 blocking antibodies or RGD peptides induced ectopic joint formation between proliferating and hypertrophic chondrocytes of the growth plate, suggesting that ␣5␤1 integrin controls the decision between cartilage differentiation and joint formation during development (13). In adult joints, increased immunostaining of ␤1 integrin was reported in osteoarthritic monkey cartilage compared with normal cartilage (14) and in human OA samples at minimally damaged locations compared with areas with more severe lesions (15).…”

Section: -Col2a1crementioning

confidence: 99%

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β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

Raducanu

Hunziker

Drosse³

et al. 2009

Journal of Biological Chemistry

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The lack of ␤1 integrins on chondrocytes leads to severe chondrodysplasia associated with high mortality rate around birth. To assess the impact of ␤1 integrin-mediated cell-matrix interactions on the function of adult knee joints, we conditionally deleted the ␤1 integrin gene in early limb mesenchyme using the Prx1-cre transgene. Mutant mice developed short limbed dwarfism and had joint defects due to ␤1 integrin deficiency in articular regions. The articular cartilage (AC) was structurally disorganized, accompanied by accelerated terminal differentiation, altered shape, and disrupted actin cytoskeleton of the chondrocytes. Defects in chondrocyte proliferation, cytokinesis, and survival resulted in hypocellularity. However, no significant differences in cartilage erosion, in the expression of matrix-degrading proteases, or in the exposure of aggrecan and collagen II cleavage neoepitopes were observed between control and mutant AC. We found no evidence for disturbed activation of MAPKs (ERK1/2, p38, and JNK) in vivo. Furthermore, fibronectin fragment-stimulated ERK activation and MMP-13 expression were indistinguishable in control and mutant femoral head explants. The mutant synovium was hyperplastic and frequently underwent chondrogenic differentiation. ␤1-null synoviocytes showed increased proliferation and phospho-focal adhesion kinase expression. Taken together, deletion of ␤1 integrins in the limb bud results in multiple abnormalities of the knee joints; however, it does not accelerate AC destruction, perturb cartilage metabolism, or influence intracellular MAPK signaling pathways. Chondrocytes of the articular cartilage (AC)2 secrete a unique set of extracellular matrix (ECM) molecules that assemble into interactive associates composed of collagens, proteoglycans (PGs), and non-collagenous glycoproteins (1). The fibrillar collagen meshwork supplies cartilage with its tensile strength, whereas the hydrated glycosaminoglycan (GAG) chains of PGs (mainly aggrecan) generate an osmotic swelling pressure that resists compressive forces. In diarthrodial joints, the molecular composition and the physical properties of the cartilage are principal determinants for the shock-absorbing function of articular surfaces upon mechanical loading. During the development of osteoarthritis (OA), an imbalance between anabolic and catabolic processes increases the proteolysis of PGs and collagens (2, 3), which eventually leads to the mechanical weakening of the AC and culminates in its progressive destruction. Physiological and pathological remodeling of the AC ECM is primarily attributed to the activities of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin-like repeat (ADAMTS) proteases (4, 5) and is controlled by the communication between the cells and their environment.An increasing amount of evidence suggests that interactions between chondrocytes and the ECM through the integrin family of heterodimeric (␣␤) transmembrane receptors play a central role in cartilage function (6). Int...

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Section: Discussionmentioning

confidence: 68%

Section: -Col2a1crementioning

confidence: 99%

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

Raducanu

Hunziker

Drosse³

et al. 2009

Journal of Biological Chemistry

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“…WNT, FGF, and Hedgehog signaling pathways network together in a variety of cellular processes, such as stem cell differentiation cascade, body axis formation, angiogenesis, organogenesis during embryogenesis, adult tissue regeneration during chronic persistent inflammation, cell fate determination and cancer cell proliferation during carcinogenesis (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

“…FGF signals are transduced through FGF receptors and FRS2 docking protein to activate RAS-RAF-MAPKK-MAPK signaling cascade as well as PI3K-AKT signaling cascade (4,5,(22)(23)(24). Hedgehog signals are transduced through Patched receptors and Smoothened signal transducers to activate transcription of target genes, such as PTCH1, SFRP1, CCND2 and FOXM1 genes, based on active form of GLI family transcription factors (6)(7)(8)(9)(25)(26)(27)(28). WNT, FGF, and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells

Katoh¹,

Katoh²

2006

Int J Mol Med

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Abstract. WNT, FGF and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. FGF16, FGF18, and FGF20 genes are targets of WNT-mediated TCF/LEF-ß-catenin-BCL9/BCL9L-PYGO transcriptional complex. SPROUTY (SPRY) and SPRED family genes encode inhibitors for receptor tyrosine kinase signaling cascades, such as those of FGF receptor family members and EGF receptor family members. Here, transcriptional regulation of SPRY1, SPRY2, SPRY3, SPRY4, SPRED1, SPRED2, and SPRED3 genes by WNT/ß-catenin signaling cascade was investigated by using bioinformatics and human intelligence (humint). Because double TCF/LEFbinding sites were identified within the 5'-promoter region of human SPRY4 gene, comparative genomics analyses on SPRY4 orthologs were further performed. SPRY4-FGF1 locus at human chromosome 5q31.3 and FGF2-NUDT6-SPATA5-SPRY1 locus at human chromosome 4q27-q28.1 were paralogous regions within the human genome. Chimpanzee SPRY4 gene was identified within NW_107083.1 genome sequence. Human, chimpanzee, rat and mouse SPRY4 orthologs, consisting of three exons, were well conserved. SPRY4 gene was identified as the evolutionarily conserved target of WNT/ ß-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian SPRY4 orthologs. Human SPRY4 mRNA was expressed in embryonic stem (ES) cells, brain, pancreatic islet, colon cancer, head and neck tumor, melanoma, and pancreatic cancer. WNT signaling activation in progenitor cells leads to the growth regulation of progenitor cells themselves through SPRY4 induction, and also to the growth stimulation of proliferating cells through FGF secretion. Epigenetic silencing and loss-of-function mutations of SPRY4 gene in progenitor cells could lead to carcinogenesis. SPRY4 is the pharmacogenomics target in the fields of oncology and regenerative medicine. IntroductionWNT, FGF, and Hedgehog signaling pathways network together in a variety of cellular processes, such as stem cell differentiation cascade, body axis formation, angiogenesis, organogenesis during embryogenesis, adult tissue regeneration during chronic persistent inflammation, cell fate determination and cancer cell proliferation during carcinogenesis (1-11).Canonical WNT signals are transduced through Frizzled receptors and LRP5/6 co-receptors to activate transcription of target genes, such as FGF18, FGF20, CCND1 and MYC, based on the transcriptional complex consisting of TCF/LEF, ß-catenin, BCL9/BCL9L, and PYGO1/PYGO2 (12-21). FGF signals are transduced through FGF receptors and FRS2 docking protein to activate RAS-RAF-MAPKK-MAPK signaling cascade as well as PI3K-AKT signaling cascade (4,5,(22)(23)(24). Hedgehog signals are transduced through Patched receptors and Smoothened signal transducers to activate transcription of target genes, such as PTCH1, SFRP1, CCND2 and FOXM1 genes, based on active form of GLI family transcription factors (6-9,25-28). WNT, FGF, and Hedgehog signaling pathways network together d...

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“…WNT, Notch, FGF, Hedgehog, and BMP signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis (1)(2)(3)(4)(5)(6)(7)(8). Canonical WNT signals are transduced through Frizzled receptors and LRP5/6 co-receptors to activate transcription of target genes, such as FGF18, FGF20, DKK1 and DKK4, based on the transcriptional complex consisting of TCF/LEF, ß-catenin, BCL9/BCL9L, and PYGO1/ PYGO2 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Comparative integromics on BMP/GDF family

Katoh¹,

Katoh²

2006

Int J Mol Med

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Abstract. WNT, Notch, FGF, Hedgehog and BMP signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP15, AMH, GDF1, GDF2, GDF3, GDF5, GDF6, GDF7, GDF8, GDF9, GDF10, GDF11, and GDF15 are BMP/GDF family genes within the human genome; however, transcriptional regulation of BMP/GDF family members by the canonical WNT signaling pathway remains unclear. We searched for the TCF/LEF-binding site within the promoter region of BMP/GDF family genes by using bioinformatics and human intelligence. Because four TCF/LEF-binding sites were identified within human GDF10 promoter, comparative genomics analyses on GDF10 orthologs were further performed. Chimpanzee GDF10 gene, encoding a 477-amino-acid protein, was identified within NW_112875.1 genome sequence. AY412135.1 was not the correct coding sequence for chimpanzee GDF10. Chimpanzee GDF10 showed 99.2%, 83.2% and 47.4% total amino-acid identity with human GDF10, mouse Gdf10 and human BMP3, respectively. RASGEF1A-GDF10-PRKG1 locus at human chromosome 10q11 and BMP3-PRKG2-RASGEF1B locus at human chromosome 4q21 were paralogous regions with insertions/deletions and recombination. Human GDF10 mRNA was expressed in fetal cochlea, fetal lung, testis, retina, pineal gland, other neural tissues, head and neck tumors, while mouse Gdf10 mRNA was expressed in fetal liver, inner ear, cerebellum, other neural tissues, prostate and blood vessels. Four TCF/LEF-binding sites in human GDF10 promoter were conserved in chimpanzee GDF10 promoter, but not in the mouse Gdf10 promoter; however, another TCF/LEF-binding site occurred in mouse Gdf10 promoter. Four bHLH-binding sites in human GDF10 promoter were conserved in chimpanzee GDF10 promoter, but only one in mouse Gdf10 promoter. Primate GDF10 promoters were divergent from mouse Gdf10 promoter. Because GDF10 was characterized as a potential target of canonical WNT signaling pathway in neural tissues, GDF10 is one of the targets of systems medicine, especially in the field of regenerative medicine.

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Coordination of chondrocyte differentiation and joint formation byα5β1 integrin in the developing appendicular skeleton

Cited by 96 publications

References 38 publications

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells

Comparative integromics on BMP/GDF family

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