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Open Access Research article

Disrupting the Indian hedgehog signaling pathway in vivo attenuates surgically induced osteoarthritis progression in Col2a1-CreER T2 ; Ihhfl/fl mice

Jingming Zhou1, Qian Chen1, Beate Lanske2, Braden C Fleming1, Richard Terek1, Xiaochun Wei3, Ge Zhang4, Shaowei Wang13, Kai Li13 and Lei Wei13*

Author Affiliations

1 Department of Orthopedics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA

2 Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA

3 Department of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, People’s Republic of China

4 Hong Kong Baptist University, Baptist University Road, Kowloon Tong, Kowloon, Hong Kong SAR, People’s Republic of China

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Arthritis Research & Therapy 2014, 16:R11  doi:10.1186/ar4437

Published: 15 January 2014

Abstract

Introduction

Previous observations implicate Indian hedgehog (Ihh) signaling in osteoarthritis (OA) development because it regulates chondrocyte hypertrophy and matrix metallopeptidase 13 (MMP-13) expression. However, there is no direct genetic evidence for the role of Ihh in OA, because mice with cartilage or other tissue-specific deletion of the Ihh gene die shortly after birth. We evaluated the role of Ihh in vivo via a Cre-loxP-mediated approach to circumvent the early death caused by Ihh deficiency.

Methods

To evaluate the role of Ihh in OA development, Ihh was specifically deleted in murine cartilage using an Ihh conditional deletion construct (Col2a1-CreERT2; Ihhfl/fl). The extent of cartilage degradation and OA progression after Ihh deletion was assessed by histological analysis, immunohistochemistry, real-time PCR and in vivo fluorescence molecular tomography (FMT) 2 months after OA was induced by partial medial meniscectomy. The effect of Ihh signaling on cartilage was compared between Ihh-deleted mice and their control littermates.

Results

Only mild OA changes were observed in Ihh-deleted mice, while control mice displayed significantly more cartilage damage. Typical OA markers such as type X collagen and MMP-13 were decreased in Ihh-deleted mice. In vivo FMT demonstrated decreased cathepsins and MMP activity in knee joints of animals with deletion of Ihh.

Conclusions

These findings support the protective role of Ihh deletion in surgically induced OA. Thus, our findings suggest the potential to develop new therapeutic strategies that can prevent and treat OA by inhibiting Ihh signaling in chondrocytes.