School of Chinese Medicine
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.
Source Publication Title
Arthritis Research and Therapy
© Zhou et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The project was supported by grant R01 AR059142 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, grants R01 CA166089 and P20GM104937 from the National Institute of General Medical Sciences, grants 81071495 and 81171676 from the National Natural Science Foundation of China, SXNSF grant 2011011042 and the Arthritis National Research Foundation.
Link to Publisher's Edition
Zhou, J., Chen, Q., Lanske, B., Fleming, B., Terek, R., Wei, X., Zhang, G., Wang, S., Li, K., & Wei, L. (2014). Disrupting the Indian hedgehog signaling pathway in vivo attenuates surgically induced osteoarthritis progression in Col2a1-CreER T2 ; Ihhfl/fl mice. Arthritis Research and Therapy, 16, R11. https://doi.org/10.1186/ar4437