A role for IGF-II in cartilage development and disease.
Abstract: Proper cartilage development is critical for normal postnatal long bone growth, however, precise mechanisms how early postnatal long bone growth is regulated have not been fully understood. Here, we demonstrate that IGF-II is required for postnatal cartilage development and long bone growth. The Igf-II null bone has reduced longitudinal and lateral growth, delayed secondary ossification ... read morecenter formation and altered prehypertrophic and hypertrophic zones. Moreover, the Igf-II null bone exhibits reduced perichondrial cell proliferation and chondrogenic differentiation. Significantly, this phenotype is not a simple delay of growth since the length-matched Igf-II null bone is thinner but exhibits a more mature growth plate than the wildtype counterpart. Thus, we show that IGF-II is indispensable for proper postnatal cartilage development and long bone growth. Osteoarthritis (OA) is a highly prevalent chronic joint disease characterized by articular cartilage destruction with local inflammation. However, currently there are no satisfactory therapeutic options to treat OA. Here, we demonstrate that ectopic IGF-II expression inhibits IL-1β activity in vitro and surgery-induced OA in murine model. IGF-II inhibits IL-1β-induced NF-κB activity and catabolic gene expression. Our data indicates phospholipase C (PLC) mediates IGF-II effects on chondrocytes. In vivo, ectopic IGF-II expression lead to enhanced cartilage matrix integrity and reduced osteophyte formation as well as subchondral bone sclerosis. Therefore, our results suggest that IGF-II can promote cartilage integrity and halt knee joint destruction in OA. Macrolide antibiotics have recently been found to have anti-inflammatory activities, but their effects on OA are unknown. The objective of this study is to investigate the effect of the macrolide antibiotic erythromycin on cartilage under inflammatory conditions and OA. We demonstrate chondroprotective activities of erythromycin in vitro and in chemically induced OA model. In vitro, EM inhibits IL-1β and LPS-mediated catabolic gene expression and NF-κB activity. Furthermore, EM has inhibitory effects on the positive regulatory loop between IL-1β and TLR4 signaling. In vivo, regional differences in cartilage matrix destruction were observed in MIA-injected mouse knee joints. EM treatment inhibited MIA-induced cartilage matrix destruction as well as synovitis in the synovium. Thus, this study implicates the chondroprotective activity of EM may be harnessed to treat OA.
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisors: Li Zeng, and Victor Hatini.
Committee: Ira Herman, Clifford Rosen, and Henry Kronenberg.
Keyword: Cellular biology.read less