title: Disrupting the Indian hedgehog signaling pathway in vivo attenuates surgically induced osteoarthritis progression in Col2a1-CreERT2; Ihhfl/fl mice.
abstract: BACKGROUND
  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.
authors.forename: Jingming
authors.initials: J
authors.lastname: Zhou
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.forename: Braden C
authors.initials: BC
authors.lastname: Fleming
authors.forename: Richard
authors.initials: R
authors.lastname: Terek
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Wei
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Shaowei
authors.initials: S
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D061346:Laser Capture Microdissection; D051379:Mice; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D053823:Hedgehog Proteins