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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-CreER   T2  ; Ihh fl/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.

Disrupting the Indian hedgehog signaling pathway in vivo attenuates surgically induced osteoarthritis progression in Col2a1-CreERT2; Ihhfl/fl mice