title: Insulin-Like Growth Factor II (IGF-II) Inhibits IL-1β-Induced Cartilage Matrix Loss and Promotes Cartilage Integrity in Experimental Osteoarthritis.
abstract: Osteoarthritis (OA) is a widespread chronic joint disease characterized by articular cartilage destruction and accompanied by pain and disability. In this study, we found that the expression of Insulin-like Growth Factor II (IGF-II) was reduced in articular cartilage in human OA patients as well as in the murine experimental OA model of destabilization of the medial meniscus (DMM). In primary human articular chondrocytes, ectopic expression of lentiviral IGF-II inhibited pro-inflammatory cytokine IL-1β-induced NF-κB activation as well as catabolic gene expression. Interestingly, IGF-II did not significantly alter the phosphorylation states of ERK1/2 or Akt, which are kinases typically activated by IGF-I. Instead, it induced the activity of phospholipase C (PLC) and a PLC inhibitor blocked the inhibitory activity of IGF-II against IL-1β, suggesting that this activity is mediated through PLC. Furthermore, IGF-II increased cartilage matrix levels and decreased MMP13 protein expression in explanted human OA cartilage cultures in vitro. In the in vivo DMM model, intraarticular injection of lentiviral IGF-II led to enhanced cartilage matrix levels and decreased MMP13 protein expression, as well as reduced osteophyte formation and subchondral bone sclerosis. Therefore, our results suggest that IGF-II can promote cartilage integrity and halt knee joint destruction in OA.
authors.affiliation: Program in Cellular, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts, 02111.|Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts, 02111.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Uchimura
authors.affiliation: Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts, 02111.
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Foote
authors.affiliation: Department of Orthopaedic Surgery, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts, 02111.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Smith
authors.affiliation: Department of Orthopaedic Surgery, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts, 02111.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Matzkin
authors.affiliation: Program in Cellular, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts, 02111.|Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts, 02111.|Department of Orthopaedic Surgery, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts, 02111.
authors.forename: Li
authors.initials: L
authors.lastname: Zeng
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000235:genetics; D008592:Menisci, Tibial / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: C035170:IGF2 protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; D007335:Insulin-Like Growth Factor II; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse
keywords: CARTILAGE; DMM; IGF-II; IL-1β; KNEE JOINT; NF-κB; OSTEOARTHRITIS (OA)