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Enhanced activity of transforming growth factor ?1 (TGF-?1) bound to cartilage oligomeric matrix protein.

ABSTRACT: Cartilage oligomeric matrix protein (COMP) is an important non-collagenous cartilage protein that is essential for the structural integrity of the cartilage extracellular matrix. The repeated modular structure of COMP allows it to "bridge" and assemble multiple cartilage extracellular matrix components such as collagens, matrilins, and proteoglycans. With its modular structure, COMP also has the potential to act as a scaffold for growth factors, thereby affecting how and when the growth factors are presented to cell-surface receptors. However, it is not known whether COMP binds growth factors. We studied the binding interaction between COMP and TGF-?1 in vitro and determined the effect of COMP on TGF-?1-induced signal transduction in reporter cell lines and primary cells. Our results demonstrate that mature COMP protein binds to multiple TGF-?1 molecules and that the peak binding occurs at slightly acidic pH. These interactions were confirmed by dual polarization interferometry and visualized by rotary shadow electron microscopy. There is cation-independent binding of TGF-?1 to the C-terminal domain of COMP. In the presence of manganese, an additional TGF-?-binding site is present in the TSP3 repeats of COMP. Finally, we show that COMP-bound TGF-?1 causes increased TGF-?1-dependent transcription. We conclude that TGF-?1 binds to COMP and that TGF-?1 bound to COMP has enhanced bioactivity.

SUBMITTER: Haudenschild DR

PROVIDER: S-EPMC3234822 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Enhanced activity of transforming growth factor β1 (TGF-β1) bound to cartilage oligomeric matrix protein.

Haudenschild Dominik R DR Hong Eunmee E Yik Jasper H N JH Chromy Brett B Mörgelin Matthias M Snow Kaylene D KD Acharya Chitrangada C Takada Yoshikazu Y Di Cesare Paul E PE

The Journal of biological chemistry 20110922 50

Cartilage oligomeric matrix protein (COMP) is an important non-collagenous cartilage protein that is essential for the structural integrity of the cartilage extracellular matrix. The repeated modular structure of COMP allows it to "bridge" and assemble multiple cartilage extracellular matrix components such as collagens, matrilins, and proteoglycans. With its modular structure, COMP also has the potential to act as a scaffold for growth factors, thereby affecting how and when the growth factors ...[more]

PMID: 21940632

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Project description:BACKGROUND:Chronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescent. The disease mechanisms are unknown. Previous studies have suggested elevated plasma levels of several cytokines, but a recent meta-analysis of 38 articles found that of 77 different cytokines measured in plasma, transforming growth factor beta (TGF-?) was the only one that was elevated in patients compared to controls in a sufficient number of articles. In the present study we therefore compared the plasma levels of the three TGF-? isoforms in adolescent CFS patients and healthy controls. In addition, the study explored associations between TGF-? levels, neuroendocrine markers, clinical markers and differentially expressed genes within the CFS group. METHODS:CFS patients aged 12-18 years (n = 120) were recruited nation-wide to a single referral center as part of the NorCAPITAL project (ClinicalTrials ID: NCT01040429). A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls (n = 68) were recruited from local schools. The three isoforms of TGF-? (TGF-?1, TGF-?2, TGF-?3) were assayed using multiplex technology. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings. Whole blood gene expression was assessed by RNA sequencing in a subgroup of patients (n = 29) and controls (n = 18). RESULTS:Plasma levels of all three isoforms of TGF-? were equal in the CFS patients and the healthy controls. Subgrouping according to the Fukuda and Canada 2003 criteria of CFS did not reveal differential results. Within the CFS group, all isoforms of TGF-? were associated with plasma cortisol, urine norepinephrine and urine epinephrine, and this association pattern was related to fatigue score. Also, TGF-?3 was related to expression of the B cell annotated genes TNFRSF13C and CXCR5. CONCLUSIONS:Plasma levels of all TGF-? isoforms were not altered in adolescent CFS. However, the TGF-? isoforms were associated with neuroendocrine markers, an association related to fatigue score. Furthermore, TGF-?3 might partly mediate an association between plasma cortisol and B cell gene expression. Trial registration Clinical Trials NCT01040429.

Dataset Information

Enhanced activity of transforming growth factor ?1 (TGF-?1) bound to cartilage oligomeric matrix protein.

Publications

Enhanced activity of transforming growth factor β1 (TGF-β1) bound to cartilage oligomeric matrix protein.

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