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This article is part of the supplement: Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

Poster presentation

TGF-β signaling induces SnoN to suppress BMP-induced hypertrophic maturation of chondrocytes

Shingo Maeda1*, Ichiro Kawamura12, Yasuhiro Ishidou1, Katsuyuki Imamura12, Masahiro Yokouchi2 and Setsuro Komiya12

  • * Corresponding author: Shingo Maeda

Author Affiliations

1 Department of Medical Joint Materials, Kagoshima University, Kagoshima, 890-8544, Japan

2 Department of Orthopaedic Surgery, Kagoshima University, Kagoshima, 890-8544, Japan

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Arthritis Research & Therapy 2012, 14(Suppl 1):P41  doi:10.1186/ar3642

The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/14/S1/P41


Published:9 February 2012

© 2012 Maeda et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background

Loss of TGF-β signaling in mice leads to promoted hypertrophic conversion of articular chondrocytes, which process is suggested to be linked to progression of osteoarthritis (OA). However, the molecular mechanisms by which TGF-β signaling inhibits chondrocyte maturation remain unclear. We screened for mediators downstream of TGF-β signaling to inhibit chondrocyte hypertrophy.

Materials and methods

We induced choncrocyte differentiation of ATDC5 cells with BMP-2. A TGF-β type I receptor inhibitor compound SB431542 was applied to inhibit endogenous TGF-β signaling. Expression of differentiation markers was evaluated by real-time RT-PCR and immunoblot. The function of SnoN was studied by stable overexpression and siRNA-knockdown approaches. Organ culture system using mouse embryo metatarsal bone was employed to study the roles of TGF-β signaling and SnoN in chondrocyte maturation.

Results

BMP-induced expression of Col10a1 gene, a specific marker for hypertrophic chondrocytes, was further up-regulated dramatically, upon treatment with SB431542. In metatarsal bone organ culture, zone of calcified matured chondrocytes was expanded upon SB431542 application. Expression of Id1 gene, the direct target of BMP Smads, was enhanced by SB431542, although the phosphorylation (activated status) of BMP-Smads-1/5/8 was not influenced by SB431542 application. Therefore, BMP signaling seemed to be blocked by TGF-β signaling at the level beneath the phosphorylation process of BMP-Smads. We evaluated expression profile of BMP signal-inhibitors, and found that SnoN was the only gene which expression was induced upon TGF-β treatment, while was inhibited by SB431542 application. Indeed, knockdown of SnoN resulted in enhanced hypertrophic maturation of ATDC5 cells, and overexpression of SnoN suppressed it. To evaluate in vivo contribution of SnoN in cartilage cell hypertrophy, we studied expression of SnoN protein by immunohistochemistry. In mouse growth plate, SnoN was present only in prehypertrophic chondrocytes, but excluded from hypertrophic zone. In human OA specimens, SnoN was positive around ectopic hypertrophic chondrocytes of moderate OA cartilages, whereas SnoN was not detected in severe-graded OA cartilages. These data support the idea that SnoN inhibits hypertrophic conversion of chondrocytes in vivo, as well as in vitro.

Conclusions

Our results suggest that SnoN suppresses hypertrophic transition of chondrocytes, as a mediator of TGF-β signaling, to prevent the progression of OA.