Abstract
IntroductionPrevious 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.MethodsTo 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.ResultsOnly 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.ConclusionsThese 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.
Highlights
Previous observations implicate Indian hedgehog (Ihh) signaling in osteoarthritis (OA) development because it regulates chondrocyte hypertrophy and matrix metallopeptidase 13 (MMP-13) expression
Our interest in the present study was to evaluate the role of Ihh in OA development by knocking down Ihh in chondrocytes to obtain more direct evidence that Ihh signaling is critical to OA progression
Our findings are in agreement with those of Lin et al, who reported that human cartilage explants treated with Hh blocking agents exhibited decreased expression of type X collagen and Matrix metallopeptidase (MMP)-13, but that Ihh ligand stimulation induced the expression of these two genes [5]
Summary
Previous observations implicate Indian hedgehog (Ihh) signaling in osteoarthritis (OA) development because it regulates chondrocyte hypertrophy and matrix metallopeptidase 13 (MMP-13) expression. 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. Cartilage degradation is induced by matrix metallopeptidases (MMPs), which are expressed by hypertrophic chondrocytes. Similar to this process, cartilage degradation in OA is mediated by MMPs [14,15,16]. Our interest in the present study was to evaluate the role of Ihh in OA development by knocking down Ihh in chondrocytes to obtain more direct evidence that Ihh signaling is critical to OA progression
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