Post-translational Processing of Bovine Chondromodulin-I

Azizan, Azliyati; Holaday, Nicole; Neame, Peter J.

doi:10.1074/jbc.m009967200

Cited by 27 publications

(26 citation statements)

References 24 publications

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“…Mature human ChM-I (120 amino acids) is also secreted from chondrocytes as a C-terminal fragment of a type II transmembrane protein (334 amino acids) after cleavage at its furin processing site (Arg-Glu-ArgArg) . No processing occurs when this precursor cleavage site is mutated to RERQ-SLVR or when the precursor cDNA is expressed in the furin-deficient CHO cell line (Azizan et al, 2001). Similarly, TeM is a putative type II transmembrane protein containing a BRICHOS domain, the functional role of which has not been fully elucidated (Sanchez-Pulido et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…We isolated and purified the factor that promoted this growth inhibition, and subsequent amino acid sequencing identified it as chondromodulin-I (ChM-I) (Hiraki et al, 1991). Transfection of ChM-I precursor cDNAs into either COS7 cells or CHO cells resulted in secretion of mature ChM-I (120 amino acids) as a 25 kDa glycoprotein following processing at the furin cleavage site of the type II membrane ChM-1 precursor protein (Azizan et al, 2001;Hiraki et al, 1997;Hiraki et al, 1999). In situ hybridization and immunohistochemistry indicated that ChM-I is specifically localized in the avascular zone of cartilage during endochondral bone formation Shukunami et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Anti-angiogenic action of the C-terminal domain of tenomodulin that shares homology with chondromodulin-I

Oshima

Sato

Tashiro

et al. 2004

Journal of Cell Science

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Tenomodulin (TeM) is a type II transmembrane glycoprotein that contains a C-terminal domain with homology to the mature, secreted form of chondromodulin-I (ChM-I), a cartilage-derived angiogenesis inhibitor. TeM transcripts have been found in hypovascular tissues such as tendons and ligaments but the biological activity of TeM has not yet been fully explored. Using an adenovirus expression system, we utilized the forced expression and subsequent secretion of the human TeM C-terminal 116 amino acids (Ad-shTeM) in human umbilical vein endothelial cells (HUVECs) to assess the anti-angiogenic properties of TeM. The C-terminal 120 amino acids of the human ChM-I precursor (Ad-shChM-I) was similarly expressed in HUVECs as a comparison study. Transduction of both Ad-shTeM and Ad-shChM-I resulted in significant impairment of the tube-forming activity of HUVECs, when cultured in Matrigel. Similarly, conditioned medium from COS7 cells, transfected with plasmid DNA encoding shTeM or shChM-I, inhibited tube formation of HUVECs when compared to medium derived from either COS7 cells transfected with control vector or from non-transfected cells. Upon infection of HUVECs with Ad-shTeM or Ad-shChM-I, DNA synthesis stimulated by vascular endothelial growth factor (VEGF) was reduced to 40-50% of normal levels. Additionally, in a modified Boyden chamber assay, migration of HUVECs in response to VEGF was significantly affected following transduction of either Ad-shTeM or Ad-shChM-I and these transduced HUVECs were found to spread well on type I collagen or fibronectin, but not on vitronectin. Furthermore, the transduction of either Ad-shTeM or Ad-shChM-I in human melanoma cells resulted in suppression of tumor growth in association with decreased vessel density in vivo. Hence, we have demonstrated that, similarly to ChM-1, the C-terminal domain of TeM exhibits both anti-angiogenic and anti-tumor activities when expressed in a secreted form.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti-angiogenic action of the C-terminal domain of tenomodulin that shares homology with chondromodulin-I

Oshima

Sato

Tashiro

et al. 2004

Journal of Cell Science

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“…SPCs convert a number of precursors of secreted proteins including members of the TGF␤ superfamily and most neural and peptide hormones (23). In cartilage a number of protein precursors are known to be processed by SPCs including BMP-like factors, collagen ␣1(XI), and chondromodulin-I (23)(24)(25)(26). Cleavage may occur intracellularly during secretion after removal of the signal peptide as shown for GDF5 in Xenopus embryogenesis and during mouse limb formation (26).…”

Section: Discussionmentioning

confidence: 99%

Ucma, a Novel Secreted Cartilage-specific Protein with Implications in Osteogenesis

Surmann‐Schmitt

Dietz

Kireva

et al. 2008

Journal of Biological Chemistry

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Here we report on the structure, expression, and function of a novel cartilage-specific gene coding for a 17-kDa small, highly charged, and secreted protein that we termed Ucma (unique cartilage matrix-associated protein). The protein is processed by a furin-like protease into an N-terminal peptide of 37 amino acids and a C-terminal fragment (Ucma-C) of 74 amino acids. Ucma is highly conserved between mouse, rat, human, dog, clawed frog, and zebrafish, but has no homology to other known proteins. Remarkable are 1-2 tyrosine sulfate residues/molecule and dense clusters of acidic and basic residues in the C-terminal part. In the developing mouse skeleton Ucma mRNA is expressed in resting chondrocytes in the distal and peripheral zones of epiphyseal and vertebral cartilage. Ucma is secreted into the extracellular matrix as an uncleaved precursor and shows the same restricted distribution pattern in cartilage as Ucma mRNA. In contrast, antibodies prepared against the processed C-terminal fragment located Ucma-C in the entire cartilage matrix, indicating that it either diffuses or is retained until chondrocytes reach hypertrophy. During differentiation of an MC615 chondrocyte subclone in vitro, Ucma expression parallels largely the expression of collagen II and decreases with maturation toward hypertrophic cells. Recombinant Ucma-C does not affect expression of chondrocyte-specific genes or proliferation of chondrocytes, but interferes with osteogenic differentiation of primary osteoblasts, mesenchymal stem cells, and MC3T3-E1 pre-osteoblasts. These findings suggest that Ucma may be involved in the negative control of osteogenic differentiation of osteochondrogenic precursor cells in peripheral zones of fetal cartilage and at the cartilage-bone interface.Elucidation of molecular mechanisms underlying chondrocyte differentiation is not only important for our understanding of skeletal development, but also of particular interest for our knowledge on the behavior of chondrocytes following articular cartilage damage during cartilage repair and treatment of degenerative cartilage diseases. Initial steps of chondrogenesis, i.e. the formation of a cartilage blastema from limb bud mesenchymal cells, include cell condensation and onset of chondrocyte differentiation marked by the expression of cartilage-specific matrix proteins such as aggrecan, collagen II, IX, and XI and others (1, 2). These events are regulated by the orchestrated action of several growth factors including BMPs, Wnt factors, FGFs, and the transcription factors Sox5,6, and 9 (3,4). Further steps of chondrocyte growth, maturation, and replacement by bone in the growth plate of long bones, ribs, and vertebrae during endochondral ossification can be defined by the stepwise onset or decline of differentially expressed genes: collagen II and Sox9 for resting and proliferating, FGFR3 for proliferating and prehypertrophic, Ihh and PTHrP receptor for prehypertrophic, collagen X for hypertrophic, and Runx2, osteocalcin, and MMP13 for late hypertrophic chondrocytes (...

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“…Proteolytic cleavage of ChM-I by furin occurs at the C-terminal of the BRICHOS domain and leads to the secretion of the C-terminal cysteine-rich domain into the ECM. The remaining membrane bound part has a short half-life and can apparently not be detected in tissue samples (3). Processing of Tnmd has not been experimentally analyzed, but a putative protease recognition sequence RXXR was identified (4).…”

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confidence: 99%

Tenomodulin Is Necessary for Tenocyte Proliferation and Tendon Maturation

Docheva

Hunziker

Fässler

et al. 2005

Molecular and Cellular Biology

374

376

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Tenomodulin (Tnmd) is a member of a new family of type II transmembrane glycoproteins. It is predominantly expressed in tendons, ligaments, and eyes, whereas the only other family member, chondromodulin I (ChM-I), is highly expressed in cartilage and at lower levels in the eye and thymus. The C-terminal extracellular domains of both proteins were shown to modulate endothelial-cell proliferation and tube formation in vitro and in vivo. We analyzed Tnmd function in vivo and provide evidence that Tnmd is processed in vivo and that the proteolytically cleaved C-terminal domain can be found in tendon extracts. Loss of Tnmd expression in gene targeted mice abated tenocyte proliferation and led to a reduced tenocyte density. The deposited amounts of extracellular matrix proteins, including collagen types I, II, III, and VI and decorin, lumican, aggrecan, and matrilin-2, were not affected, but the calibers of collagen fibrils varied significantly and exhibited increased maximal diameters. Tnmd-deficient mice did not have changes in tendon vessel density, and mice lacking both Tnmd and ChM-I had normal retinal vascularization and neovascularization after oxygeninduced retinopathy. These results suggest that Tnmd is a regulator of tenocyte proliferation and is involved in collagen fibril maturation but do not confirm an in vivo involvement of Tnmd in angiogenesis.Tendons and ligaments connect the elements of the musculoskeletal system and are composed of a densely packed collagen-rich connective tissue able to withstand high tensile forces. Collagen type I is predominant, but collagen types III,

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Post-translational Processing of Bovine Chondromodulin-I

Cited by 27 publications

References 24 publications

Anti-angiogenic action of the C-terminal domain of tenomodulin that shares homology with chondromodulin-I

Anti-angiogenic action of the C-terminal domain of tenomodulin that shares homology with chondromodulin-I

Ucma, a Novel Secreted Cartilage-specific Protein with Implications in Osteogenesis

Tenomodulin Is Necessary for Tenocyte Proliferation and Tendon Maturation

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