Expression of Collagen-Binding Integrin Receptors in the Mammalian Sclera and Their Regulation during the Development of Myopia

McBrien, Neville A.; Metlapally, Ravikanth; Jobling, Andrew I; Gentle, Alex

doi:10.1167/iovs.05-1150

Cited by 77 publications

(74 citation statements)

References 51 publications

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“…The recombinant PIIBNP cleaved with thrombin was run in the second lane, showing the migration of the PIIBNP produced by bacteria. The third through fifth lanes show extracts from human developing limbs reacted with antibody to PIIBNP (exons [3][4][5][6][7][8]. The band that migrates at 16.1-kDa is the monomer of PIIBNP, migrating slightly slower than the recombinant form due to hydroxylation of proline residues.…”

Section: Normal Chondrocytes Have Reduced or Undetectable Receptor Inmentioning

confidence: 99%

Type IIB Procollagen NH2-propeptide Induces Death of Tumor Cells via Interaction with Integrins αVβ3 and αVβ5

Wang

Bryan

Franz

et al. 2010

Journal of Biological Chemistry

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Cartilage is resistant to tumor invasion. In the present study, we found that the NH 2 -propeptide of the cartilage-characteristic collagen, type IIB, PIIBNP, is capable of killing tumor cells. The NH 2 -propeptide is liberated into the extracellular matrix prior to deposition of the collagen fibrils. This peptide adheres to and kills cells from chondrosarcoma and cervical and breast cancer cell lines via the integrins ␣ v ␤ 5 and ␣ v ␤ 3 . Adhesion is abrogated by blocking with anti ␣ v ␤ 5 and ␣ v ␤ 3 antibodies. When ␣ v is suppressed by small intefering RNA, adhesion and cell killing are blocked. Normal chondrocytes from developing cartilage do not express ␣ v ␤ 3 and ␣ v ␤ 5 integrins and are thus protected from cell death. Morphological, DNA, and biochemical evidence indicates that the cell death is not by apoptosis but probably by necrosis. In an assay for invasion, PIIBNP reduced the number of cells crossing the membrane. In vivo, in a tumor model for breast cancer, PIIBNP was consistently able to reduce the size of the tumor.Cartilage is a unique tissue in being composed of only one cell type, chondrocytes. In addition, cartilage is avascular and resistant to tumor invasion, although the mechanism by which this occurs is unknown. Cartilage ECM 2 is predominantly made up of fibrillar type IIB collagen and the large proteoglycan aggrecan. The fibrillar collagens, types I, II, III, V, and XI, are synthesized as procollagens containing NH 2 -and COOH-terminal extension peptides that are removed prior to deposition of the collagen monomers into fibrils in the extracellular matrix (1). During the chondrogenesis phase of endochondral bone development, large amounts of type IIB collagen are synthesized as the tissue is established. Thereafter, in the cartilaginous growth plate, the cells become hypertrophic, change their predominant collagen synthesis to type X collagen, and eventually die by apoptosis. The hypertrophic cartilage is vascularized and subsequently removed by specialized osteoclasts, and the tissue is replaced by bone synthesized by osteoblasts. By this process, the cartilage provides an anlagen for bone formation (2, 3).Type II procollagen is unique among the fibrillar collagens in containing vicinal RGD motifs in the NH 2 -terminal propeptide domain encoded by exon 6 of the COL2A1 gene (supplemental Fig. 1). RGD peptides serve as the primary integrin recognition sites in extracellular matrix proteins and, as such, play an important role in regulating cell/matrix interactions required for proper cell function. Integrins are cell adhesion molecules that consist of two non-covalently associated subunits ␣ and ␤ (4). Integrins are receptors for many ECM matrix proteins, such as for collagens (The binding of substrate to integrins on the cell surface stimulates intracellular signaling to affect gene expression (outside-in signaling), and the cell can alter the expression and affinity of integrins (inside-out signaling). This bidirectional signaling controls cellular activity, such as cell-cell and ce...

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Section: Normal Chondrocytes Have Reduced or Undetectable Receptor Inmentioning

confidence: 99%

Type IIB Procollagen NH2-propeptide Induces Death of Tumor Cells via Interaction with Integrins αVβ3 and αVβ5

Wang

Bryan

Franz

et al. 2010

Journal of Biological Chemistry

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“…The sclera contains a collagen-rich extracellular matrix that undergoes significant biochemical and biomechanical remodeling during the development of myopia (3). Linkage studies of high myopia have identified potential loci MYP1 (Xq28) and MYP3 (12q21-23); these loci are within and/or near the loci of the human genome containing several genes that encode small leucine-rich proteoglycans (SLRP), 3 i.e.…”

mentioning

confidence: 99%

“…Linkage studies of high myopia have identified potential loci MYP1 (Xq28) and MYP3 (12q21-23); these loci are within and/or near the loci of the human genome containing several genes that encode small leucine-rich proteoglycans (SLRP), 3 i.e. biglycan (Xq27ter), decorin (12q21-22), lumican (12q21.…”

mentioning

confidence: 99%

“…biglycan (Xq27ter), decorin (12q21-22), lumican (12q21. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], and DSPG3 (12q21) (4 -9). Our previous study showed that certain variations (rs3759223 (C3 T)) of single nucleotide polymorphism in the lumican regulatory region may influence the promoter activities of lumican and affect fibrillogenesis in myopic eyes (10).…”

mentioning

confidence: 99%

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Knockdown of Zebrafish Lumican Gene (zlum) Causes Scleral Thinning and Increased Size of Scleral Coats

Yeh

Liu

Kao

et al. 2010

Journal of Biological Chemistry

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The lumican gene (lum), which encodes one of the major keratan sulfate proteoglycans (KSPGs) in the vertebrate cornea and sclera, has been linked to axial myopia in humans. In this study, we chose zebrafish (Danio rerio) as an animal model to elucidate the role of lumican in the development of axial myopia. The zebrafish lumican gene (zlum) spans ϳ4.6 kb of the zebrafish genome. Like human (hLUM) and mouse (mlum), zlum consists of three exons, two introns, and a TATA box-less promoter at the 5-flanking region of the transcription initiation site. Sequence analysis of the cDNA predicts that zLum encodes 344 amino acids. zLum shares 51% amino acid sequence identity with human lumican. Similar to hLUM and mlum, zlum mRNA is expressed in the eye and many other tissues, such as brain, muscle, and liver as well. Transgenic zebrafish harboring an enhanced GFP reporter gene construct downstream of a 1.7-kb zlum 5-flanking region displayed enhanced GFP expression in the cornea and sclera, as well as throughout the body. Downregulation of zlum expression by antisense zlum morpholinos manifested ocular enlargement resembling axial myopia due to disruption of the collagen fibril arrangement in the sclera and resulted in scleral thinning. Administration of muscarinic receptor antagonists, e.g. atropine and pirenzepine, effectively subdued the ocular enlargement caused by morpholinos in in vivo zebrafish larvae assays. The observation suggests that zebrafish can be used as an in vivo model for screening compounds in treating myopia.Myopia is a very common ocular disorder, which is characterized by excessive elongation of the eyeball. In Taiwan, the prevalence of myopia is about 84% of schoolchildren aged 16 -18, and the prevalence of high myopia (less than Ϫ6.0 D) at 18 years of age is 24% in girls and 18% in boys (1). In contrast, the prevalence of high myopia is much lower in Western countries, about 1% of the general population (2). These studies imply that genetic susceptibility of ethnic differences may account for the high prevalence of myopia in Taiwanese.The sclera contains a collagen-rich extracellular matrix that undergoes significant biochemical and biomechanical remodeling during the development of myopia (3). Linkage studies of high myopia have identified potential loci MYP1 (Xq28) and MYP3 (12q21-23); these loci are within and/or near the loci of the human genome containing several genes that encode small leucine-rich proteoglycans (SLRP), 3 i.e. biglycan (Xq27ter), decorin (12q21-22), lumican (12q21.3-22), and DSPG3 (12q21) (4 -9). Our previous study showed that certain variations (rs3759223 (C3 T)) of single nucleotide polymorphism in the lumican regulatory region may influence the promoter activities of lumican and affect fibrillogenesis in myopic eyes (10). Furthermore, Majava et al. (11) found that a novel single nucleotide polymorphism (c.893-105G3 A) of the lumican gene was associated with high myopia. Recently, our prospective case control study also showed that genetic variation in the regulatory domai...

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“…There are fi ve distinct categories of receptor genes namely CHRM1 to CHRM5 , which encode for fi ve different MR proteins from M1 to M5, each with distinct pharmacological properties. Ciliary body and iris sphincter express all fi ve subtypes of MR with a predominant role for the M3 subtype [138][139][140].…”

Section: Muscarinic Receptorsmentioning

confidence: 99%

Transporters and receptors in the anterior segment of the eye

Cholkar

Ray

Agrahari

et al. 2013

Ocular Transporters and Receptors

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Expression of Collagen-Binding Integrin Receptors in the Mammalian Sclera and Their Regulation during the Development of Myopia

Cited by 77 publications

References 51 publications

Type IIB Procollagen NH2-propeptide Induces Death of Tumor Cells via Interaction with Integrins αVβ3 and αVβ5

Type IIB Procollagen NH2-propeptide Induces Death of Tumor Cells via Interaction with Integrins αVβ3 and αVβ5

Knockdown of Zebrafish Lumican Gene (zlum) Causes Scleral Thinning and Increased Size of Scleral Coats

Transporters and receptors in the anterior segment of the eye

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