Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein-6 deficient mice

Fülöp, Csaba; Szántó, Sándor; Mukhopadhyay, Durba; Bárdos, Tamás; Kamath, Rajesh V.; Rugg, Marylin S.; Day, Anthony J.; Salustri, Antonietta; Hascall, Vincent C.; Glant, Tibor T.; Mikecz, Katalin

doi:10.1242/dev.00422

Cited by 363 publications

(313 citation statements)

References 36 publications

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“…In fact, the relationship between impaired cumulus cell-oocyte matrix assembly and female sterility in Tnfip6-knockout mice reveals an essential role for this protein in the formation of crosslinked HA fibers around the oocyte that is necessary for the expansion of cumulus matrix and subsequent oocyte fertilization (15).…”

Section: Discussionmentioning

confidence: 99%

“…Tnfip6-deficient mice were generated by disrupting exon 1 with the Neo r -poly(A) cassette, creating a translation stop codon at 94 bp downstream of the translation start site in the Tnfip6 gene (15). As described earlier, the only phenotype abnormality in Tnfip6-deficient mice is the infertility of the Tnfip6 Ϫ/Ϫ females (15). Using a marker-assisted speed-backcrossing protocol, heterozygous (Tnfip6 ϩ/Ϫ ) males were mated with wild-type BALB/c females.…”

Section: Methodsmentioning

confidence: 99%

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Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice

Szántó¹,

Bárdos²,

Gál³

et al. 2004

Arthritis & Rheumatism

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Objective. To gain insight into the mechanisms of the antiinflammatory effect of tumor necrosis factor ␣ (TNF␣)-induced protein 6 (Tnfip6) in arthritis, using Tnfip6-deficient animals.Methods. TNF␣-stimulated gene 6 (TSG-6) coding for Tnfip6 was disrupted. Tnfip6-deficient mice were backcrossed into proteoglycan-induced arthritis (PGIA)-susceptible BALB/c mice, and arthritis was induced by systemic immunization with cartilage proteoglycan (PG). Thioglycollate-induced sterile peritonitis was also assessed, to monitor the early events of neutrophil extravasation in wild-type and Tnfip6-deficient mice in the presence or absence of treatment with recombinant murine Tnfip6.Results. The onset of PGIA was similar, but progression and severity were significantly greater, in Tnfip6-deficient mice compared with wild-type BALB/c mice. However, this was not associated with enhanced T or B cell responses to cartilage PGs, but rather, an early and more extensive infiltration of the synovium with neutrophil leukocytes was the most prominent histopathologic feature of PGIA in Tnfip6-deficient mice. This was accompanied by elevated serum levels of interleukin-6 and amyloid A, and significantly increased activities of the enzymes plasmin, myeloperoxidase, and neutrophil elastase in the inflamed paw joints of Tnfip6-null mice, when compared with that of the wild-type littermates. Loss of control over several components of inflammation resulted in extensive and rapid cartilage degradation, bone erosion, joint ankylosis, and deformities in Tnfip6-null animals. In support of the antiinflammatory effect of Tnfip6 via the inhibition of polymorphonuclear (PMN) cell efflux, neutrophil invasion during thioglycollate-induced peritonitis was 2-fold higher in Tnfip6-deficient animals than in wild-type animals, but was dramatically suppressed by intravenous injection of recombinant murine Tnfip6.Conclusion. Tnfip6 is a multifunctional antiinflammatory protein that is produced at the site of inflammation and can be retained by the hyaluronanrich extracellular matrix. A major effect of Tnfip6 is the inhibition of the extravasation of PMN cells, predominantly neutrophils, into the site of inflammation, most likely via a CD44/hyaluronan/Tnfip6-mediated blocking mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice

Szántó¹,

Bárdos²,

Gál³

et al. 2004

Arthritis & Rheumatism

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“…His 4 replaced by Lys) and H29K (38), six new mutants (H4S, H29A, H45A, H45K, H45S, H96K) were prepared and analyzed by one-dimensional NMR and mass spectrometry as before (27); all mutants had molecular masses within 2 Da of their theoretical values. Uniformly 15 N-and 15 N, 13 C-labeled WT Link_TSG6 were produced by expression in M9 minimal medium (26). Full-length TSG-6 (Q allele) was generated as detailed previously (39).…”

Section: Methodsmentioning

confidence: 99%

Determining the Molecular Basis for the pH-dependent Interaction between the Link Module of Human TSG-6 and Hyaluronan

Blundell

Mahoney

Cordell

et al. 2007

Journal of Biological Chemistry

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TSG-6 is an inflammation-associated hyaluronan (HA)-binding protein that has anti-inflammatory and protective functions in arthritis and asthma as well as a critical role in mammalian ovulation. The interaction between TSG-6 and HA is pH-dependent, with a marked reduction in affinity on increasing the pH from 6.0 to 8.0. Here we have investigated the mechanism underlying this pH dependence using a combined approach of site-directed mutagenesis, NMR, isothermal titration calorimetry and microtiter plate assays. Analysis of single-site mutants of the TSG-6 Link module indicated that the loss in affinity above pH 6.0 is mediated by the change in ionization state of a histidine residue (His 4 ) that is not within the HA-binding site. To understand this in molecular terms, the pH-dependent folding profile and the pK a values of charged residues within the Link module were determined using NMR. These data indicated that His 4 makes a salt bridge to one side-chain oxygen atom of a buried aspartate residue (Asp 89 ), whereas the other oxygen is simultaneously hydrogen-bonded to a key HA-binding residue (Tyr 12 ). This molecular network transmits the change in ionization state of His 4 to the HA-binding site, which explains the loss of affinity at high pH. In contrast, simulations of the pH affinity curves indicate that another histidine residue, His 45 , is largely responsible for the gain in affinity for HA between pH 3.5 and 6.0. The pH-dependent interaction of TSG-6 with HA (and other ligands) provides a means of differentially regulating the functional activity of this protein in different tissue microenvironments. TSG-6,5 the secreted product of tumor necrosis factor-stimulated gene 6, is not usually expressed constitutively in healthy adult tissues but is made in response to various inflammatory mediators and growth factors, acting as a potent anti-inflammatory and chondroprotective agent (1-3). The TSG-6 protein is produced in inflammatory diseases, for example rheumatoid arthritis, osteoarthritis, and asthma (4), as well as in normal physiological processes that have inflammation-like characteristics (e.g. ovulation and cervical ripening). A number of roles for TSG-6 have been determined, including inhibition of neutrophil migration (5-7) and down-regulation of the protease network (4, 5, 8), which could help explain its protective properties in, for example, joint tissues (9 -11). In addition, TSG-6 has been implicated in the stabilization of extracellular matrix (ECM) structure, particularly by supporting the formation of cross-linked hyaluronan (HA) networks (12). TSG-6-mediated HA cross-linking has a critical role in mammalian ovulation but also occurs in inflammatory diseases (4, 13-17).TSG-6 is composed mainly of contiguous Link and CUB modules (2). Although there are currently no known ligands for the CUB module, the Link module (expressed in Escherichia coli (18,19) and termed Link_TSG6) has been shown to interact with a large number of molecules commonly found in the ECM. Not only does Link_TSG6 bind ...

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“…E-mail: droberts@helix.nih.gov.joint tissues from destruction in in vivo models (Wisniewski et al, 1996;Milner and Day, 2003;Szanto et al, 2004;Milner et al, 2006). TSG-6 is also expressed in the ovary during ovulation and plays an important role in female fertility by regulating cumulus cell-oocyte complex expansion (Fulop et al, 2003;Ochsner et al, 2003). The protein consists mainly of contiguous Link and CUB (complement component Clr/Cls, Uegf, and bone morphogenetic protein 1) domains.…”

Section: Introductionmentioning

confidence: 99%

TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly

et al. 2008

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Human plasma fibronectin binds with high affinity to the inflammation-induced secreted protein TSG-6. Fibronectin binds to the CUB_C domain of TSG-6 but not to its Link module. TSG-6 can thus act as a bridging molecule to facilitate fibronectin association with the TSG-6 Link module ligand thrombospondin-1. Fibronectin binding to TSG-6 is divalent cation-independent and is conserved in cellular fibronectins. Based on competition binding studies using recombinant and proteolytic fragments of fibronectin, TSG-6 binding localizes to type III repeats 9-14 of fibronectin. This region of fibronectin contains the Arg-Gly-Asp sequence recognized by α5β1 integrin, but deletion of that sequence does not prevent TSG-6 binding, and TSG-6 does not inhibit cell adhesion on fibronectin substrates mediated by this integrin. This region of fibronectin is also involved in fibronectin matrix assembly, and addition of TSG-6 enhances exogenous and endogenous fibronectin matrix assembly by human fibroblasts. Therefore, TSG-6 is a high affinity ligand that can mediate fibronectin interactions with other matrix components and modulate some interactions of fibronectin with cells.

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Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein-6 deficient mice

Cited by 363 publications

References 36 publications

Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice

Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice

Determining the Molecular Basis for the pH-dependent Interaction between the Link Module of Human TSG-6 and Hyaluronan

TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly

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